Pyrrolotriazine compounds and methods of inhibiting tam kinases

ABSTRACT

Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments comprising such compounds, and methods of using such compounds to treat cancer.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the filing date of U.S.Provisional Application No. 62/570,381, filed Oct. 10, 2017, the entirecontent of which is hereby incorporated by reference herein.

BACKGROUND

The TAM receptor tyrosine kinases (TYRO3, AXL and MERTK; the “TAMkinases”) constitute a family of receptor tyrosine kinases (RTKs) thatplay several important roles in normal macrophage physiology, includingregulation of cytokine secretion and clearance of apoptotic cells. TAMkinases have also been suggested as emerging targets in cancer therapy(see, e.g., Akalu et al., Immunol. Rev. 276(1):165-177, 2017).

SUMMARY

The present disclosure provides compounds represented by structuralFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is a bond, —O—, —S(O)₂—, —N(R⁶)—, —N(R⁶)—C(O)—*, —C(O)—N(R⁶)—*,—N(R⁶)—S(O)₂—*, —S(O)₂—N(R⁶)—*, —O—C(O)—*, —C(O)—O—*, —O—C(O)—N(R⁶)—*,—NR⁶—C(O)—NR⁶—*, or —(C1-C6 alkyl)-P(O)—*, wherein “*” is a point ofattachment to R¹;

R¹ is hydrogen, —C₁-C₆ alkyl, —(C₀-C₆ alkylene)-aryl, —(C₀-C₆alkylene)-heteroaryl, —(C₀-C₆ alkylene)-heterocyclyl, or —(C₀-C₆alkylene)-carbocyclyl, wherein any alkyl or alkylene portion of R¹ isoptionally substituted with up to six (e.g., 1, 2, 3, 4, 5, or 6)independently selected monovalent substituents and any aryl, heteroaryl,heterocyclyl, or carbocyclyl portion of R¹ is optionally substitutedwith up to four (e.g., 1, 2, 3, or 4) independent substituents;

L² is a bond, —O—, —S(O)₂—, —N(R⁶)—, —N(R⁶)—C(O)—†, C(O)—N(R⁶)—†,—N(R⁶)—S(O)₂—†, —S(O)₂—N(R⁶)—†, —O—C(O)—†, —O—C(O)—N(R⁶)—†,—N(R⁶)—C(O)—NR⁶—†, or —(C₁-C₆ alkyl)-P(O)—†, wherein “†” is a point ofattachment to R²;

R² is hydrogen, —C₁-C₆ alkyl, —(C₀-C₆ alkylene)-aryl, —(C₀-C₆alkylene)-heteroaryl, —(C₀-C₆ alkylene)-heterocyclyl, or —(C₀-C₆alkylene)-carbocyclyl, wherein any alkyl or alkylene portion of R² isoptionally substituted with up to six (e.g., 1, 2, 3, 4, 5, or 6)independently selected monovalent substituents and any aryl, heteroaryl,heterocyclyl, or carbocyclyl portion of R¹ is optionally substitutedwith up to four (e.g., 1, 2, 3, or 4) independently selectedsubstituents;

R³ is hydrogen, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, —(C₂-C₆alkylene)-O—(C₁-C₆ alkyl), —(C₀-C₈ alkylene)-aryl, —(C₀-C₈alkylene)-carbocyclyl, —(C₀-C₈ alkylene)-heterocyclyl, or —(C₀-C₈alkylene)-heteroaryl, wherein any alkyl, alkenyl, alkynyl or alkyleneportion of R³ is optionally substituted with up to six (e.g., 1, 2, 3,4, 5, or 6) independently selected monovalent substituents and any aryl,heteroaryl, heterocyclyl, or carbocyclyl portion of R³ is optionallysubstituted with up to four (e.g., 1, 2, 3, or 4) independently selectedsubstituents;

R⁴ is hydrogen, halogen, —CN, a 4- to 8-membered heterocyclyl, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —C₃-C₈ cycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl) or —O—(C₃-C₈ cycloalkyl), where the cycloalkyl andheterocyclyl are optionally substituted with up to 4 independentlyselected substituents;

R⁵ is hydrogen, halogen, —CN, a 4- to 8-membered heterocyclyl, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), or —O—(C₃-C₈ cycloalkyl), where the cycloalkyl andheterocyclyl are optionally substituted with up to 4 independentlyselected substituents; and

R⁶ is hydrogen, —C₁-C₆ alkyl, aryl, heteroaryl, heterocyclyl, orcarbocyclyl, wherein R⁶ is optionally substituted with up to fourindependently selected substituents.

In some embodiments, a compound and/or composition described herein maybe used to inhibit a TAM kinase, at least at a site of interest (e.g.,in a tissue, in a cell, in a subcellular location, etc.). In someembodiments, a provided compound and/or composition may be used toinhibit cell proliferation. In some embodiments, a provided compoundand/or composition may be used to inhibit activity of one or morekinases, such as a kinase of the TAM kinase family. In some embodiments,a provided compound and/or composition may be used to inhibit anactivity of one or more kinases, such as MERTK, AXL and TYRO3. In someembodiments, a provided compound and/or composition has increasedspecificity for TAM kinases relative to FLT3. In some embodiments, aprovided compound and/or composition may be used to inhibit TAM kinasesand does not inhibit FLT3 (e.g., does not substantially inhibit FLT3).

In some embodiments, a provided compound and/or composition is contactedwith and/or administered to cells, such as cancer cells. In someembodiments, the cancer cells may be cells of a breast cancer, ovariancancer, glioblastoma, pancreatic ductal adenocarcinoma, non-small celllung cancer (NSCLC), colorectal cancer (CRC), a blood cancer (e.g., aleukemia or lymphoma), gastric cancer, prostate cancer, pituitaryadenoma, melanoma or rhabdomyosarcoma. In some embodiments, the compoundand/or composition is administered to a cancer resistant to a checkpointinhibitor. In some embodiments, a provided compound and/or compositionis co-administered with a checkpoint inhibitor. In some embodiments, aprovided compound and/or composition is administered to a cancerassociated with elevated myeloid infiltration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a table of exemplary compounds of Formula I.

FIG. 2 is a table showing the ¹H NMR spectra peak values, the massspectrometry values, and the general synthetic schemes utilized to makeeach of the compounds in FIG. 1.

FIG. 3 is a graph demonstrating the effect on tumor volume afteradministration of Compound 124 (as shown in FIG. 1) alone, an anti-PD-1antibody alone, or those two agents in combination.

DETAILED DESCRIPTION

The “TAM receptors” (named for TYRO3, AXL, and MERTK) are a family ofreceptor tyrosine kinases (RTKs) that play important roles in normalmacrophage physiology, including regulation of cytokine secretion andclearance of apoptotic cells. The TAM kinases are characterized by twoimmunoglobulin-like domains, which mediate ligand-binding, and twofibronectin type III domains at the extracellular N-terminus; by asingle-pass transmembrane domain; and by a cytoplasmic tail containing atyrosine kinase domain. TAM kinases are expressed in many systems,including the nervous, reproductive, vascular, and immune systems(Rothlin et al., Annu. Rev. Immunol. 33:355-391, 2015). Expressionwithin the immune system is heterogeneous among macrophage subsets,being mostly restricted to anti-inflammatory M2 macrophages, whichcontribute to the immunosuppression present in the tumormicroenvironment. By inhibiting TAM kinases on tumor-infiltratingmacrophages, the immunosuppressive environment can be reduced, therebyincreasing effector killer immune cell function and promoting tumorregression.

Current CD8+ T cell- and natural killer (NK) cell-directedimmunotherapies have shown promise but only in a limited percentage ofpatients. The reason for this limitation is not well understood, but itmay be that the immunosuppressive environment is inhibiting efficacy.Since M2 macrophages contribute significantly to this environment,reversing the M2 phenotype may increase responsiveness to CD8+ T cell-and NK cell-directed immunotherapies. Therefore, we expect the TAMkinase inhibitors disclosed herein to be useful in treating cancerswhere checkpoint inhibitors have shown limited efficacy, andparticularly where there is high myeloid infiltration. Methods of usingthe TAM kinase inhibitors disclosed herein, alone or in combination withcheckpoint inhibitors, to treat cancer, including pancreatic ductaladenocarcinomas, ovarian cancers, triple-negative breast cancers(TNBCs), glioblastomas, and colorectal cancers, are within the scope ofthe invention and are discussed further below.

In addition to the expression profiles referenced above, over- orectopic expression of one or more TAM kinases has been reported inmultiple human cancer types, including brain cancer (e.g.,glioblastoma), breast cancer (e.g., TNBC), colon and colorectal cancers,gastric cancer, leukemias, liver cancer, lung cancer (e.g., NSCLC),lymphomas, ovarian cancer, pituitary adenomas, prostate cancer, renalcancer, rhabdomyosarcomas, skin cancer (e.g., melanoma), and thyroidmalignancies (see, e.g., Graham et al., Nature Reviews Cancer14(12):769-785, 2014 and Linger et al., Adv. Cancer Res. 100:35, 2008).The overexpression of MERTK in at least some cancer cells results inincreased survival and resistance to apoptosis, resulting in oncogenesis(Nguyen et al., J. Biol. Chem. 289(37):25737-25749, 2014; and Linger etal., Blood 122(9):1599-1609, 2013). Elevated TAM kinase expression hasalso been associated with cancer progression, resistance to targetedtherapies, and metastasis (see, e.g., Debruyne et al., Oncogene35(28):3681-3691, 2016; Giles et al., Mol. Cancer Ther.12(11):2541-2558, 2013; and Meyer et al., Sci. Signal. 6(287), 2013). Atleast one report has indicated TAM kinase signaling in NK cells promotesmetastasis (Paolino et al., Nature 407(7493):508-512, 2014). While thecompositions and methods of the invention are not limited to those thatachive a beneficial therapeutic outcome by any particular mechanism ofaction, it may be that at least some of the anti-tumoral activityresults from inhibition of TAM kinase signaling on NK cells.

The following definitions apply to the compositions and methodsdescribed herein unless the context clearly indicates otherwise. It willbe clear to one of ordinary skill in the art that the definitions applyto grammatical variants of these terms, some of which are particularlymentioned below (e.g., “administration” and “administering”). Thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed. Additionally, general principles of organic chemistry are describedin “Organic Chemistry,” Thomas Sorrell, University Science Books,Sausalito, 1999, and “March's Advanced Organic Chemistry,” 5^(th) Ed.,Ed. Smith and March, John Wiley & Sons, New York, 2001.

The term “about,” when used in reference to a value, signifies any valueor range of values within plus-or-minus 10% of the stated value (e.g.,within plus-or-minus 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of thestated value). For example, a dose of about 10 mg means any dose as lowas 10% less than 10 mg (9 mg), any dose as high as 10% more than 10 mg(11 mg), and any dose or dosage range therebetween (e.g., 9-11 mg;9.1-10.9 mg; 9.2-10.8 mg; and so on).

The term “administration” and variants thereof, such as “administering,”typically refer to the administration of a compound described herein ora composition containing it (e.g., a pharmaceutical composition) to asubject (e.g., a human patient) or system (e.g., a cell- or tissue-basedsystem maintained ex vivo). One of ordinary skill in the art will beaware of a variety of routes that may, in appropriate circumstances, beutilized for administration to a subject or system. For example, theroute of administration may be oral (i.e., by swallowing apharmaceutical composition) or parenteral. More specifically, the routeof administration can be bronchial (e.g., by bronchial instillation), bymouth (i.e., oral), dermal (which may be or comprise topical applicationto the dermis or intradermal, interdermal, or transdermaladministration), intragastric or enteral (i.e., directly to the stomachor intestine, respectively), intramedullary, intramuscular, intranasal,intraperitoneal, intrathecal, intravenous (or intra-arterial),intraventricular, by application to or injection into a specific organ(e.g., intrahepatic), mucosal (e.g., buccal, rectal, sublingual, orvaginal), subcutaneous, tracheal (e.g., by intratracheal instillation),or ocular (e.g., topical, subconjunctival, or intravitreal).Administration can involve intermittent dosing (e.g., a plurality ofdoses separated in time) and/or periodic dosing (e.g., doses separatedby a common period of time (e.g., every so many hours, daily, weekly,twice per week, etc.)). In other embodiments, administration may involvecontinuous dosing (e.g., perfusion) for a selected period of time.

The terms “aliphatic” and “aliphatic group” mean a branched, unbranched(i.e., straight-chain) or cyclic hydrocarbon group that is substitutedor unsubstituted and either completely saturated or having one or moreunits of unsaturation. The cyclic aliphatic group is a monocyclic orbicyclic hydrocarbon group that is not aromatic and that has a singlepoint of attachment to the molecule (i.e., compound) of which it is apart. We may refer to such cyclic groups as “cycloaliphatic,”“carbocycle,” “carbocyclyl,” or “cycloalkyl”). Unless otherwisespecified, aliphatic groups contain 1-10 aliphatic carbon atoms(“C₁-C₁₀”). Aliphatic groups in the present compounds can contain, forexample, 1-6 aliphatic carbon atoms (“C₁-C₆”); 1-5 aliphatic carbonatoms (“C₁-C₅”); 1-4 aliphatic carbon atoms (“C₁-C₄”); 1-3 aliphaticcarbon atoms (“C₁-C₃”); or 1-2 aliphatic carbon atoms (“C₁-C₂”). In someembodiments, a cycloaliphatic hydro carbon group has 3-6 aliphaticcarbon atoms (“C₃-C₆”). Thus, suitable aliphatic groups include, but arenot limited to, substituted or unsubstituted alkyl, alkenyl, and alkynylgroups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl and (cycloalkyl)alkenyl.

The term “alkyl” means a branched or unbranched (i.e., straight) chain,saturated, monovalent hydrocarbon group containing 1 to 10 carbon atoms.Suitable alkyl groups include methyl, ethyl, n- and iso-propyl, n-,sec-, iso- and tert-butyl, and neopentyl. The term “alkylene” means abranched or unbranched (i.e., straight chain) bivalent alkyl group.Exemplary alkylenes include —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —CH₂CH(CH₃)—,—CH(CH₃)CH₂—, etc. In some embodiments, an “alkylene chain” is apolymethylene group, i.e., —(CH₂)_(n)—, wherein n is a positive integer,preferably from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6, or 1-4, 1-3, 1-2,2-3, etc.). A substituted alkylene chain is a bivalent alkyl group inwhich one or more hydrogen atoms are replaced with a substituent.

The term “alkenyl” means a monovalent branched or unbranched (i.e.,straight) chain of, unless otherwise specified, 2 to 10 carbon atoms(“C₂-C₁₀”) containing at least one carbon-carbon double bond. Alkenylgroups are exemplified by ethenyl, propenyl, butenyl, pentenyl, hexenyl,and so forth. The term “alkenylene” means a bivalent alkenyl group. Asubstituted alkenylene chain is a bivalent alkenyl group containing atleast one double bond in which one or more hydrogen atoms are replacedwith a substituent.

The term “alkynyl” means a monovalent branched or unbranched (i.e.,straight) chain of from 2 to 10 carbon atoms (“C₂-C₁₀”) containing atleast one carbon-carbon triple bond. Suitable alkynyl groups includeethynyl, propynyl, butynyl, pentynyl, hexynyl, and so forth.

The terms “aryl” and “aryl ring” describe monocyclic, bicyclic andtricyclic ring systems having a total of six to 14 ring atoms, each ofwhich is carbon. Further, at least one ring in the system is aromatic,and each ring in the system contains three to seven ring members. Incertain embodiments, these terms refer to an aromatic ring system thatincludes, but is not limited to, phenyl (Ph), biphenyl, naphthyl, andanthracyl, which may bear one or more substituents. In some embodiments,an aromatic ring is fused to one or more non-aromatic rings (e.g.,indanyl, naphthimidyl, and ortetrahydronaphthyl).

Two events or entities are “associated” with one another if one or morefeatures of the first (e.g., its presence, level and/or form) arecorrelated with a feature of the second. For example, a first entity(e.g., a polypeptide (e.g., a TAM kinase or a combination thereof), geneexpression profile, genetic signature (i.e., a single or combined groupof genes in a cell with a uniquely characteristic pattern of geneexpression), metabolite, or event (e.g., myeloid infiltration)) isassociated with a particular disease, if its presence, level and/or formcorrelates with the incidence of, severity of, and/or susceptibility tothe disease (e.g., a cancer disclosed herein). Associations aretypically assessed across a relevant population. Two or more entitiesare physically “associated” with one another if they interact, directlyor indirectly, so that they are and/or remain in physical proximity withone another in a given circumstance (e.g., within a cell maintainedunder physiological conditions (e.g., within cell culture) or within apharmaceutical composition). Entities that are physically associatedwith one another can be covalently linked to one another ornon-covalently associated by, for example, hydrogen bonds, van der Waalsforces, hydrophobic interactions, magnetism, or combinations thereof.

The terms “binding” and variants thereof (such as “bound” and “bind(s)”)typically refer to a covalent or non-covalent association of two or moreentities (e.g., a compound and an agent within a pharmaceuticalcomposition or a compound and its target within a cell). “Direct”binding occurs when the two entities physically contact one another(e.g., through a chemical bond) whereas indirect binding occurs when atleast one of the entities physically contact one or more intermediateentities that bring them into physical proximity with one another (e.g.,within a complex). Binding can be assessed in a variety of contexts(e.g., in full or partial isolation or in more complex, naturallyoccurring or model systems (e.g., in a tissue, organ, or cell)).

The term “biologically active” describes an agent (e.g., a compounddescribed herein) that produces an observable biological effect orresult in a biological system or model thereof (e.g., in a human, otheranimal, or a system maintained in vitro). The “biological activity” ofsuch an agent can result from binding between the agent and a target(e.g., a TAM kinase), and it may result in modulation (e.g., induction,enhancement, or inhibition) of a biological pathway or event (e.g.,cellular activity (e.g., immunostimulation) or proliferation). Thepresence of biological activity and, optionally, its extent, can beassessed using known and/or standard methods to detect an immediate ordownstream product or event associated with the biological activity.

The term “biological sample” refers to a sample obtained or derived froma biological source of interest (e.g., a tissue or organism (e.g., ananimal or human patient) or cell culture). The biological sample cancontain a biological cell, tissue or fluid or any combination thereof.For example, a biological sample can be or can comprise ascites; blood;blood cells; bodily fluid(s), any of which may include or exclude cells;bone marrow; cerebrospinal fluid (CSF); feces; flexural fluid; freefloating nucleic acids; gynecological fluids; immune infiltrates; lymph;peritoneal fluid; plasma; saliva; sputum; surgically-obtained specimens;tissue scraped or swabbed from the skin or a mucus membrane (e.g., inthe nose, mouth, or vagina); tissue or fine needle biopsy samples;urine; washings or lavages such as a ductal lavage or broncheoalveolarlavage; or other body fluids, tissues, secretions, and/or excretions. Abiological sample may include cancer cells or immune cells, such as NKcells and/or macrophages, which are found in many tissues and organs,including the spleen and lymph nodes. Cells (e.g., NK cells,macrophages, and cancer cells) within the sample may have been obtainedfrom an individual for whom a treatment is intended. Samples used in theform in which they were obtained may be referred to as “primary”samples, and samples that have been further manipulated (e.g., by addingor removing one or more components of the sample) may be referred to as“secondary” or “processed” samples. Such processed samples may containor be enriched for a particular cell type (e.g., a TAM kinase-expressingcell such as a macrophage or tumor cell), cellular component (e.g., amembrane fraction), or cellular material (e.g., one or more cellularproteins, including one or more of the TAM kinases, DNA, or RNA (e.g.,mRNA), which may have been subjected to amplification).

The term “cancer” refers to a disease in which cells exhibit an aberrantgrowth phenotype characterized by loss of control of cell proliferationto an extent that will be detrimental to a patient having the disease. Acancer can be classified by the type of tissue in which it originated(histological type) and/or by the primary site in the body in which thecancer first developed. Based on histological type, cancers aregenerally grouped into six major categories: carcinomas; sarcomas;myelomas; leukemias; lymphomas; and mixed types. A cancer treated asdescribed herein may be of any one of these types and may comprise cellsthat are precancerous (e.g., benign), malignant, pre-metastatic,metastatic, and/or non-metastatic. A patient who has a malignancy ormalignant lesion has a cancer. The present disclosure specificallyidentifies certain cancers to which its teachings may be particularlyrelevant, and one or more of these cancers may be characterized by asolid tumor or by a hematologic tumor, which may also be known as ablood cancer (e.g., a type described herein). Although not all cancersmanifest as solid tumors, we may use the terms “cancer cell” and “tumorcell” interchangeably to refer to any malignant cell.

The term “carrier” refers to a diluent, adjuvant, excipient, or othervehicle with which a compound or composition is administered. Thecarrier can be a sterile or sterilizable liquid, such as a water (e.g.,water for injection) or a natural or synthetic oil (e.g., apetroleum-based or mineral oil, an animal oil, or a vegetable oil (e.g.,a peanut, soybean, sesame, or canola oil)). The carrier can also be asolid; a liquid that includes one or more solid components (e.g., asalt, for example, a “normal saline”); a mixture of solids; or a mixtureof liquids.

The term “comparable” refers to two or more items (e.g., agents,entities, situations, sets of conditions, etc.) that are not identicalto one another but are sufficiently similar to permit comparisontherebetween so that one of ordinary skill in the art will appreciatethat conclusions may reasonably be drawn based on differences orsimilarities observed. In some embodiments, comparable sets ofconditions, circumstances, individuals, or populations are characterizedby a plurality of substantially identical features and one or a smallnumber of varied features. One of ordinary skill in the art willunderstand, in context, what degree of identity is required in any givencircumstance for two or more items to be considered comparable. Forexample, two items are comparable to one another when they have incommon a sufficient number and type of substantially identical featuresto warrant a reasonable conclusion that any differences in resultsobtained or phenomena observed with the items are caused by or areindicative of the variation in those features that are varied. In someembodiments, a comparable item serves as a “control.” For example, a“control subject/population” can be an untreated individual/populationwho is afflicted with the same disease as an individual/population beingtreated.

The term “combination therapy” refers to those situations in which asubject is exposed to two or more therapeutic regimens (e.g., two ormore therapeutic agents) to treat a single disease (e.g., a cancer). Thetwo or more regimens may be administered simultaneously or sequentially(e.g., all “doses” of a first regimen are administered prior toadministration of any dose(s) of a second regimen by the same or adifferent route of administration). For clarity, combination therapydoes not require that individual agents be administered together in asingle composition (or even necessarily at the same time), although insome embodiments, two or more agents (e.g., compounds described herein)may be administered together in a single composition or even as acombination compound (e.g., associated in a single chemical complex orcovalent entity).

The term “compound” means a chemical compound (e.g., a compoundrepresented by a structural Formula depicted herein, a sub-genusthereof, or a species thereof). Any given compound can be biologicallyand/or therapeutically active (e.g., when contained in a pharmaceuticalcomposition in a therapeutically effective amount) and can be providedand/or utilized (e.g., used in a biological assay, administered to apatient, incorporated into a medicament, or otherwise used as describedherein) in any of a variety of forms: unless the context clearlyindicates otherwise, the references herein to a “compound” encompass thecompound per se, a stereoisomeric form thereof (e.g., an optical and/orstructural isomer), a tautomer, or an isotopic form thereof. Thestereoisomers of any referenced or depicted structure can be enantiomersand diastereomers (e.g., cis/trans isomers and conformational isomers).These include the R and S configurations for each asymmetric center, Zand E double bond isomers, and Z and E conformational isomers.Compositions containing a single type of stereochemical isomer as wellas enantiomeric, diastereomeric, and geometric (or conformational)mixtures of the present compounds are within the scope of the invention.Where a compound contains an isotopic substitution, it can be, e.g., ²Hor ³H for H; ¹¹C, ¹³C or ¹⁴C for ¹²C; ¹³N or ¹⁵N for ¹⁴N; ¹⁷O or ¹⁸O for¹⁶O; ³⁶Cl for ³⁵C; ¹⁸F for ¹⁹F; ¹³¹I for ¹²⁷I; etc. Such compounds haveuse, for example, as analytical tools, as probes in biological assays,and/or as therapeutic or prophylactic agents for use in accordance withthe present invention. In particular, an isotopic substitution ofdeuterium (²H) for hydrogen is known to potentially slow downmetabolism, shift metabolism to other sites on the compound, slow downracemization and/or have other effects on the pharmacokinetics of thecompound that may be therapuetically beneficial.

The terms “dosage form,” “formulation,” and “preparation” are used torefer to compositions containing a compound or other biologically and/ortherapeutically active agent that are suitable for administration to apatient. The term “unit dosage form” refers to a physically discreteunit of a compound or other biologically and/or therapeutically activeagent (e.g., a therapeutic or diagnostic agent) formulated foradministration to a subject. Typically, each such unit contains apredetermined quantity of the active agent, which may be the amountprescribed for a single dose (i.e., an amount expected to correlate witha desired outcome when administered as part of a therapeutic regimen) ora fraction thereof. One of ordinary skill in the art will appreciatethat the total amount of a therapeutic composition or agent administeredto a particular subject is determined by one or more attendingphysicians and may involve administration of multiple unit dosage forms.

The term “dosing regimen” refers to the unit dosage form(s) administeredto, or prescribed for, a subject, and typically includes more than onedose separated by periods of time (e.g., as described elsewhere herein).The dosage form(s) administered within a dosing regimen can be of thesame unit dose amount or of different amounts. For example, a dosingregimen can comprises a first dose in a first dose amount, followed byone or more additional doses in a second dose amount that is the same asor different from the first dose amount.

The term “halogen” means F, Cl, Br, or I.

The term “heteroalkyl” refers to an alkyl group in which one or morecarbon atoms is replaced with a heteroatom selected from oxygen (O),sulfur (S), or nitrogen (N).

The term “heteroar-,” used alone or as part of a e.g. longer term suchas “heteroaryl” or “heteroaryl ring/group,” refer to optionallysubstituted (i.e., substituted or unsubstituted) mono-, bi-, ortricyclic chemical groups having 5 to 14 ring atoms (e.g., 5, 6, or 9ring atoms); 6, 10, or 14π electrons shared in a cyclic array; and inaddition to carbon atoms, from one to five heteroatoms. A heteroarylgroup is both heterocyclic and aromatic and can be, without limitation,thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, and pteridinyl. In a heteroar-, a heteroaryl ring can also befused to one or more aryl, cycloaliphatic, or heterocyclyl rings (e.g.,it can be indolyl, isoindolyl, benzothienyl, benzofuranyl,dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, 5,6,7,8-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one). When a heteroaryl ring is fused toan aryl ring, the term “heteroaro” is used to refer to that heteroarylring.

The term “heteroatom” refers to oxygen, sulfur, nitrogen, phosphorus,and silicon, including any oxidized forms of those atoms; and thequaternized form of any basic nitrogen or a substitutable nitrogen of aheterocyclic ring; for example N

As used immediately above and elsewhere herein, “

,” appearing across or at the end of a bond indicates a point ofattachment between two atoms. For example, in the ring structures justshown,

indicates that the ring carbon or ring nitrogen is bound to anundepicted structure on which the ring is a substituent.

The terms “heterocycle,” “heterocyclyl,” and “heterocyclicradical/ring,” are used interchangeably and refer to a stable 4- to7-membered monocyclic, 7-11-membered bicyclic, or 10-16-memberedtricyclic heterocyclic chemical structure that is either saturated orpartially unsaturated, and that has, in addition to carbon atoms, one ormore (e.g., 1-4) heteroatoms, as defined herein. A heterocyclic ring canbe attached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure, and any of the ring atoms can beoptionally substituted (i.e., substituted or unsubstituted). As shownabove and for example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen moiety may be N (as in 3,4-dihydro-2H-pyrrolyl-), NH (as inpyrrolidinyl-), NR{circumflex over ( )} (as in N-substituted2-pyrrolidinyl) or ⁺NR{circumflex over ( )} (as in N-substituted1-pyrrolidinyl). Examples of a saturated or partially unsaturatedheterocycle include, without limitation, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl, aswell as chemical structures in which a heterocyclyl ring is fused to oneor more aryl, heterocyclyl, or cycloaliphatic rings (e.g., indolinyl,3H-indolyl, chromanyl, 1,2,3,4-tetrahydroisoquinolinyl and1,2,3,4-tetrahydroquinolinyl). When a heterocyclic ring is fused to anaryl ring, we refer to that heterocyclic ring using the term“heterocyclo.” A “saturated heterocyclic ring” refers to a saturatedring having one or more heteroatoms, wherein the ring is monocyclic orfused to one or more saturated cycloaliphatic rings.

“Improve(s),” “increase(s)” or “reduce(s)/decrease(s)” are terms used tocharacterize the manner in which a value has changed relative to areference value. For example, a measurement obtained from a patient (ora biological sample obtained therefrom) prior to treatment can beincreased or reduced/decreased relative to that measurement obtainedduring or after treatment in the same patient, a control patient, onaverage in a patient population, or biological sample(s) obtainedtherefrom. The value may be improved in either event, depending onwhether an increase or decrease is associated with a positivetherapeutic outcome.

The term “inhibitor” refers to an agent, including a compound describedherein, whose presence (e.g., at a certain level or in a certain form)correlates with a decrease in the expression or activity of anotheragent (i.e., the inhibited agent or target) or a decrease in theoccurrence of an event (e.g., tumor progression or metastasis). In someembodiments, an inhibitor exerts its influence on a target by binding tothe target, directly or indirectly. In other embodiments, an inhibitorexerts its influence by binding and/or otherwise altering a regulator ofthe target, so that the expression and/or activity of the target isreduced. Inhibition can be assessed in silico, in vitro (e.g., in acell, tissue, or organ culture or system), or in vivo (e.g., in apatient or animal model).

A compound described herein can contain one or more “optionallysubstituted” moieties. By “substituted,” we mean that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure issubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. As a designated moiety within an optionally substitutedcompound may be, but is not necessarily, substituted, such moieties aredescribed as substituted when a suitable substituent is present and“unsubstituted” when any such substituent is absent. For example,“optionally substituted phenyl” encompasses “substituted phenyl” and“unsubstituted phenyl;” an “optionally substituted alkyl” encompasses“substituted alkyl” and “unsubstituted alkyl;” a substitutable carbonatom may be a “substituted carbon atom” or an “unsubstituted carbonatom;” and so forth. Combinations of substituents are those that resultin the formation of stable or chemically feasible compounds. The term“stable” refers to compounds that are not substantially altered whensubjected to conditions that allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of anoptionally substituted group can be, independently, deuterium, halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂, —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂, —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄—C(O)—N(R^(∘))—S(O)₂—R^(∘); —C(NCN)NR^(∘) ₂,—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂, —C(S)NR^(∘) ₂, —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘)₂, —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂,—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂, —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NOR^(∘))NR^(∘) ₂, —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —P(O)(OR^(∘))₂, —OP(O)R^(∘) ₂, —OP(O)(OR^(∘))₂,—OP(O)(OR^(∘))R^(∘); —SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁-4 straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁-6 aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 3-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from N, O, or S, or, notwithstanding thedefinition above, two independent occurrences of R^(∘), taken togetherwith their intervening atom(s), form a 3-12-membered saturated,partially unsaturated, or aryl mono- or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,which may be substituted as defined below.

Suitable monovalent substituents on R^(∘)(or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), may be, independently, halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂, —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁-4straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁-4 aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 independently selected heteroatoms(e.g., N, O, or S). Suitable divalent substituents on a saturated carbonatom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of anoptionally substituted moiety include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, and—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic, which may be substituted as definedbelow, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 independently selected heteroatoms(e.g., N, O, or S). Suitable divalent substituents that are bound tovicinal substitutable carbons of an optionally substituted moietyinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic, which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 independently selected heteroatoms(e.g., N, O, or S).

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 independently selected heteroatoms (e.g., N, O, orS).

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 3-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on an aliphatic group of R^(†) are, independently,halogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from N, O, or S.Suitable divalent substituents on a saturated carbon atom of R^(†)include ═O and ═S.

“Partially unsaturated” refers to a ring moiety other than an aryl orheteroaryl that includes at least one double or triple bond and mayinclude multiple sites of unsaturation.

A “pharmaceutical composition” is a composition in which an active agent(e.g., an active pharmaceutical ingredient (e.g., a compound) isformulated together with one or more pharmaceutically acceptablecarriers. The active agent can be present in a unit dose amountappropriate for administration in a therapeutic regimen that shows astatistically significant probability of achieving a predeterminedtherapeutic effect when administered to a relevant population. Thepharmaceutical composition may be specially formulated foradministration in solid or liquid form, including forms made for oral orparenteral administration. For oral administration, the pharmaceuticalcomposition can be formulated, for example, as an aqueous or non-aqueoussolution or suspension or as a tablet or capsule. For systemicabsorption through the mouth, the composition can be formulated forbuccal administration, sublingual administration, or as a paste forapplication to the tongue. For parenteral administration, thecomposition can be formulated, for example, as a sterile solution orsuspension for subcutaneous, intramuscular, intravenous, intra-arterial,intraperitoneal, or epidural injection. Pharmaceutical compositionscomprising an active agent (e.g., a compound described herein) can alsobe formulated as sustained-release formulations or as a cream, ointment,controlled-release patch, or spray for topical application. Creams,ointments, foams, gels, and pastes can also be applied to mucusmembranes lining the nose, mouth, vagina, and rectum. Any of thecompounds described herein and any pharmaceutical composition containingsuch a compound may also be referred to as a “medicament.”

The terms “patient” and “subject” refer to any organism to which acompound described herein is administered in accordance with the presentinvention e.g., for experimental, diagnostic, prophylactic, and/ortherapeutic purposes. Typical subjects include animals (e.g., mammalssuch as mice, rats, rabbits, non-human primates, and humans; insects;worms; etc.). In some embodiments, a subject is suffering from a disease(e.g., a cancer) described herein.

The term “pharmaceutically acceptable,” when applied to a carrier usedto formulate a composition disclosed herein (e.g., a pharmaceuticalcomposition), means a carrier that is compatible with the otheringredients of the composition and not deleterious to a patient (e.g.,it is non-toxic in the amount required and/or administered (e.g., in aunit dosage form)).

The term “pharmaceutically acceptable salt” refers to a salt that is,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans (e.g., patients) and lower animals withoutunacceptable toxicity, irritation, allergic response and the like, andthat can be used in a manner commensurate with a reasonable benefit/riskratio. Many pharmaceutically acceptable salts are well known in the art(see, e.g., Berge et al., J. Pharm. Sci. 66:1-19, 1977; incorporatedherein by reference) and, as noted, the invention encompassespharmaceutically acceptable salt forms of each compound describedherein.

A “polypeptide” is a polymer of amino acid residues, regardless oflength, source, or post-translational modification; it encompasses butis not limited to full-length, naturally occurring proteins. Where apolypeptide is bound by (e.g., specifically bound) or otherwiseinteracts with a composition described herein, we may refer to thatpolypeptide as the composition's “target.”

The terms “prevent(s),” “prevention,” and “prophylaxis/prophylactic,”when used in connection with the occurrence of disease (e.g., a cancer),refer to reducing the risk of developing the disease and/or to delayingthe onset of one or more signs or symptoms thereof. Prevention can beconsidered complete when onset has been delayed for a predefined periodof time.

The term “reference” describes a standard or control relative to which acomparison is made. For example, in some embodiments, an agent, animal,cell, individual, population, sample (e.g., biological sample), sequenceor value of interest is compared with a reference or control agent,animal, cell, individual, population, sample, sequence or value. In someembodiments, a reference or control is tested and/or determinedsubstantially simultaneously with the testing or determination ofinterest. In some embodiments, a reference or control is a historicalreference or control, optionally embodied in a tangible medium.Typically, as would be understood by one of ordinary skill in the art, areference or control is determined or characterized under comparableconditions or circumstances to those under assessment, and one ofordinary skill in the art will appreciate when sufficient similaritiesare present to justify reliance on and/or comparison to a particularpossible reference or control.

The term “response” with respect to a treatment may refer to anybeneficial alteration in a subject's condition that occurs as a resultof, or correlates with, treatment. Such an alteration may includestabilization of the condition (e.g., prevention of deterioration thatwould have taken place in the absence of the treatment), amelioration ofsymptoms of the condition, and/or improvement in the prospects for cureof the condition, etc. The response may be a cellular response (e.g., atumor's response) and can be measured using a wide variety of criteria,including clinical criteria and objective criteria, known in the art.Techniques for assessing a response include, but are not limited to,assay assessment, clinical examination, positron emission tomography,X-ray, CT scan, MRI, ultrasound, endoscopy, laparoscopy, assessing thepresence or level of tumor markers in a sample obtained from a subject,cytology, and/or histology. Regarding measuring tumor response, methodsand guidelines for assessing response to treatment are discussed inTherasse et al. (J. Natl. Cancer Inst., 92(3):205-216, 2000). The exactresponse criteria can be selected by one of ordinary skill in the art inany appropriate manner, provided that when comparing groups of cancersand/or patients, the groups to be compared are assessed based on thesame or comparable criteria for determining response rate.

The term “specific,” as used herein with reference to an agent (e.g., acompound) having an activity (e.g., inhibition of a target), means thatthe agent discriminates between potential target entities or states. Forexample, an agent binds “specifically” to its intended target (orotherwise specifically inhibits its target) if it preferentially bindsor otherwise inhibits the expression or activity of that target in thepresence of one or more alternative targets. Although the invention isnot so limited, a specific and direct interaction can depend uponrecognition of a particular structural feature of the target (e.g., anepitope, a cleft, or a binding site). Specificity need not be absolute;the degree of specificity need only be enough to result in an effectivetreatment without unacceptable side effects. The specificity of an agentcan be evaluated by comparing the effect of the agent on an intendedtarget or state relative to its effect on a distinct target or state.The effects on the intended and distinct targets can each be determinedor the effect on the intended target can be determined and compared to areference standard developed at an earlier time (e.g., a referencespecific binding agent or a reference non-specific binding agent). Insome embodiments, the agent does not detectably bind the competingalternative target under conditions in which it detectably (and,preferably, significantly) binds its intended target and/or does notdetectably inhibit the expression or activity of the competing targetunder conditions in which it detectably (and, preferably, significantly)inhibits the expression or activity of its intended target. In someembodiments, a compound of the invention may exhibit, with respect toits target(s), a higher on-rate, lower off-rate, increased affinity,decreased dissociation, and/or increased stability compared with thecompeting alternative target, and any of these parameters can beassessed in methods of the invention.

The term “substantially” refers to the qualitative condition ofexhibiting a characteristic or property of interest to a total ornear-total extent or degree. One of ordinary skill in the art willunderstand that biological and chemical phenomena rarely, if ever, go tocompletion and/or proceed to completeness or achieve or avoid anabsolute result. The term “substantially” is therefore used herein tocapture the potential lack of completeness inherent in many biologicaland chemical phenomena. For example, a chemical reaction may becharacterized as substantially complete even though the yield is wellbelow 100%. Certain features may also be described as being“substantially identical,” meaning they are about the same and/orexhibit about the same activity. For example, two nearly identicalcompounds that produce about the same effect on an event (e.g., cellularproliferation) may be described as substantially similar. With regard tothe purity of a compound or composition, “substantially pure” is definedbelow.

An individual who is “susceptible to” a disease (e.g., a cancer) has agreater than average risk for developing the disease. In someembodiments, such an individual does not display any symptoms of thedisease. In some embodiments, such an individual has not been diagnosedwith the disease. In some embodiments, such an individual has beenexposed to conditions associated with development of the disease (e.g.,exposure to a carcinogen). In some embodiments, a risk of developing adisease is a population-based risk.

A “sign or symptom is reduced” when one or more objective signs orsubjective symptoms of a particular disease are reduced in magnitude(e.g., intensity, severity, etc.) and/or frequency. A delay in the onsetof a particular sign or symptom is one form of reducing the frequency ofthat sign or symptom. Reducing a sign or symptom can be achieved by,e.g., a “therapeutically active” compound.

A “therapeutic regimen” refers to a dosing regimen that, whenadministered across a relevant population, is correlated with a desiredtherapeutic outcome.

A “therapeutically effective amount” refers to an amount that producesthe desired effect for which it is administered. In some embodiments,the term refers to an amount that is sufficient, when administered to apopulation suffering from or susceptible to a disease in accordance witha therapeutic dosing regimen, to treat the disease. One of ordinaryskill in the art will appreciate that the term “therapeuticallyeffective amount” does not in fact require successful treatment beachieved in a particular individual. Rather, a therapeutically effectiveamount may be that amount that provides a particular desiredpharmacological response in a significant number of subjects whenadministered to patients in need of such treatment. In some embodiments,reference to a therapeutically effective amount may be a reference to anamount measured in one or more specific tissues (e.g., a tissue affectedby the disease) or fluids (e.g., blood, saliva, urine, etc.).

The term “treatment” (also “treat(s)” or “treating”) refers to any useof a pharmaceutical composition or administration of a therapy thatpartially or completely alleviates, ameliorates, relives, inhibits,reduces the severity of, and/or reduces incidence of one or more signsor symptoms of a particular disease (e.g., a cancer). In someembodiments, such treatment may be of a subject who exhibits only earlysigns or symptoms of the disease. Alternatively or additionally, suchtreatment may be of a subject who exhibits one or more established signsor symptoms of the relevant disease. In some embodiments, treatment maybe of a subject who has been diagnosed as suffering from the relevantdisease. The term “treatment” is distinguished from “prophylaxis,” whichrelates, for example, to delaying onset of one or more signs or symptomsof the particular disease and/or to administration to a subject who doesnot exhibit signs of the relevant disease and/or to a subject known tohave one or more susceptibility factors that are statisticallycorrelated with increased risk of development of the relevant disease.

The term “unsaturated,” as used herein with regard to a compound or amoiety therein, means that the compound or the moiety therein has one ormore units of unsaturation (e.g., a carbon-carbon double bond (i.e.,—C═C—) or a carbon-carbon triple bond (i.e., —C≡C)).

As described herein, compounds within the present invention can have astructure represented by Formula I:

(stated more simply, “a compound of Formula I”), wherein each of L¹, R¹,L², R², R³, R⁴, and R⁵ is as defined herein and further described inclasses and subclasses, both singly and in combination.

In some embodiments, when L² is a bond and R² is aryl or heteroaryl, R³is other than optionally substituted phenyl, and the compound is otherthan:

In some embodiments, L¹ is a bond, —O—, —S(O)₂—, —N(R⁶)—, —N(R⁶)—C(O)—*,—C(O)—N(R⁶)—*, —N(R⁶)—S(O)₂—*, —S(O)₂—N(R⁶)—*, —O—C(O)—*, —C(O)—O—*,—O—C(O)—N(R⁶)—*, —NR⁶—C(O)—NR⁶—*, or —(C₁-C₆ alkyl)-P(O)—*, wherein “*”is a point of attachment to R¹. In some embodiments, L¹ is a bond.

In some embodiments, R¹ is hydrogen, C₁-C₆ alkyl, —(C₀-C₆alkylene)-aryl, —(C₀-C₆ alkylene)-heteroaryl, —(C₀-C₆alkylene)-heterocyclyl, or —(C₀-C₆ alkylene)-carbocyclyl, wherein anyalkyl or alkylene portion of R¹ is optionally substituted with up to sixindependently selected monovalent substituents and any aryl, heteroaryl,heterocyclyl, or carbocyclyl portion of R¹ is optionally substitutedwith up to four independent substituents. In some embodiments, R¹ isheteroaryl (e.g., —(C₀ alkylene)-heteroaryl) substituted with one tofour independent substituents.

In some embodiments, L² is a bond, —O—, —S(O)₂—, —N(R⁶)—, —N(R⁶)—C(O)—†,C(O)—N(R⁶)—†, —N(R⁶)—S(O)₂-†, —S(O)₂—, —N(R⁶)—†, —C(O)—†, —O—C(O)—†,—N(R⁶)—†, —N(R⁶)—C(O)—NR⁶—†, or —(C₁-C₆ alkyl)-P(O)—†, wherein “†” is apoint of attachment to R².

In some embodiments, R² is hydrogen, C₁-C₆ alkyl, —(C₀-C₆alkylene)-aryl, —(C₀-C₆ alkylene)-heteroaryl, —(C₀-C₆alkylene)-heterocyclyl, or —(C₀-C₆ alkylene)-carbocyclyl, wherein anyalkyl or alkylene portion of R² is optionally substituted with up to six(e.g., 1, 2, 3, 4, 5, or 6) independently selected monovalentsubstituents and any aryl, heteroaryl, heterocyclyl, or carbocyclylportion of R¹ is optionally substituted with up to four independentsubstituents. In some compounds of these embodiments, R² is aryl (e.g.,—(C₀ alkylene)-aryl), heteroaryl (e.g., —(C₀ alkylene)-heteroaryl),-heterocyclyl (e.g., —(C₀ alkylene)-heterocyclyl), or carbocyclyl (e.g.—(C₀ alkylene)-carbocyclyl), where any aryl, heteroaryl, heterocyclyl,or carbocyclyl is optionally substituted with up to four independentsubstituents.

In some embodiments, R³ is hydrogen, —C₁-C₈ alkyl, —C₂-C₈ alkenyl,—C₂-C₈ alkynyl, —(C₂-C₆ alkylene)-O—(C₁-C₆ alkyl), —(C₀-C₈alkylene)-aryl, —(C₀-C₈ alkylene)-carbocyclyl, —(C₀-C₈alkylene)-heterocyclyl, or —(C₀-C₈ alkylene)-heteroaryl, wherein anyalkyl, alkenyl, alkynyl or alkylene portion of R³ is optionallysubstituted with up to six (e.g., 1, 2, 3, 4, 5, or 6) independentlyselected monovalent substituents and any aryl, heteroaryl, heterocyclyl,or carbocyclyl portion of R³ is optionally substituted with up to fourindependent substituents. In some compounds, R³ is C₂-C₄ alkyl, (C₂-C₄alkylene)-O—(C₁-C₃ alkyl), —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-carbocyclyl, —(C₀-C₄ alkylene)-heterocyclyl, or —(C₀-C₄alkylene)-heteroaryl, where any alkyl, alkenyl, alkynyl or alkyleneportion of R³ is optionally substituted with up to six independentlyselected monovalent substituents; and any aryl, heteroaryl,heterocyclyl, or carbocyclyl portion of R³ is optionally substitutedwith up to four independent substituents.

In some embodiments, R⁴ is hydrogen, halogen, —CN, a 4- to 8-memberedheterocyclyl, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₃-C₈ cycloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl) or —O—(C₃-C₈ cycloalkyl), whereinthe cycloalkyl and heterocyclyl is optionally substituted with up tofour independently selected substituents. In some embodiments, R⁴ ishydrogen.

In some embodiments, R⁵ is hydrogen, halogen, —CN, a 4- to 8-memberedheterocyclyl, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,—O—(C₁-C₆ alkyl) —O—(C₁-C₆ haloalkyl), or —O—(C₃-C₈ cycloalkyl), whereinthe cycloalkyl and heterocyclyl is optionally substituted with up to 4independently selected substituents. In some embodiments, R⁵ ishydrogen.

In some embodiments, R⁶ is hydrogen, —C₁-C₆ alkyl, aryl, heteroaryl,heterocyclyl, or carbocyclyl, wherein R⁶ is optionally substituted withup to four independent substituents. In some embodiments, R⁶ is hydrogenor —C₁-C₄ alkyl.

In some embodiments, L¹ is a bond, —NH—, —O—, or —C(O)—NH—*. In someembodiments, L¹ is a bond.

In some embodiments, R¹ is carbocyclyl, heterocyclyl, heteroaryl, aryl,or C₁-C₆ alkyl; and, in any one or more of these embodiments, R¹ can beoptionally substituted.

In some embodiments, R¹ is methyl, cyclopentyl, cyclohexyl,cyclohex-3-en-4-yl, phenyl, piperidin-4-yl, piperazin-1-yl,piperidin-1-yl, piperidin-4-yl, pyridin-3-yl, pyrrolidin-3-yl,3,6-dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, or1,2,3,6-tetrahydropyridin-4-yl; and in any one or more of theseembodiments, R¹ can be optionally substituted.

In some embodiments, R¹ is piperidin-3-yl, pyrazol-3-yl, pyrazol-4-yl,1,2,3-triazol-4-yl, imidazol-4-yl, isoindolin-4-yl, isoindolin-5-yl,pyridin-2-yl, pyridin-4-yl, pyrimdin-5-yl, oxazol-5-yl, indolin-5-yl,indolin-6-yl, indol-6-yl, pyridazin-5-yl, pyrrolidin-1-yl,morpholin-4-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl,8-azabicyclo[3.2.1]oct-2-ene-3-yl, 8-azabicyclo[3.2.1]octan-3-yl,thien-3-yl, thien-2-yl, 3,6-dihydropyridin-4-yl, benzo[d]imidazol-5-yl,benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, isoxazol-4-yl, orimidazo[1,2-a]pyridin-6-yl; and in any one or more of these embodiments,R¹ is optionally substituted.

In some embodiments, R¹ is pyrazol-4-yl, or pyridin-4-yl, wherein R¹ issubstituted with fluoro, —CN; C₁-C₄ alkyl optionally substituted withone or more substitutents selected from cyano, hydroxy, and halo;—(C₀-C₃ alkylene)-COOH, —O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl), —(C₁-C₃alkylene)-O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —(C₀-C₄alkylene)-S(O)₂—(C₁-C₃ alkyl), —S(O)(═NH)—(C₁-C₄ alkyl), —C(O)NH₂,—(C₀-C₃ alkylene)-C(O)—NH—(C₁-C₄ alkyl), —(C₀-C₃ alkylene)-C(O)—O—(C₁-C₄alkyl), —(C₀-C₃ alkylene)-C(O)—(C₁-C₄ alkyl), —(C₀-C₃alkylene)-C(O)—NH—S(O)₂—(C₁-C₄ alkyl), —NH—(C₁-C₄ alkyl),—S(O)₂—NH—(C₁-C₄ alkyl), -(cyclopropyl)-C(O)—NH—(C₁-C₄ alkyl),-(cyclopropyl)-(cyano-substituted C₁-C₃ alkyl), —(C₀-C₄ alkylene)-aryl,—(C₀-C₄ alkylene)-heteroaryl, —O-heteroaryl, —(C₀-C₄alkylene)-heterocyclyl, —(C₀-C₃ alkylene)-C(O)-heterocyclyl,—C(O)—(C₀-C₃ alkylene)-heterocyclyl, —(C₀-C₃ alkylene)-NH-heterocyclyl,—(C₀-C₃ alkylene)-C(O)—NH-heterocyclyl,-(cyclopropyl)-C(O)-(heterocyclyl), —O-heterocyclyl, wherein the aryl,heterocyclyl or heteroaryl portion of an R¹ substituent is optionallysubstituted. In some aspects of these embodiments the aryl, heterocyclylor heteroaryl portion of an R¹ substituent is optionally substitutedwith one or more substituents selected from —OH, —CN, ═O, C₁-C₄ alkyl,halo-substituted C₁-C₄ alkyl, hydroxy-substituted C₁-C₄ alkyl,—S(O)₂—(C₁-C₄ alkyl), —S(O)₂-cyclopropyl, cyclopropyl, —S(O)₂—(C₁-C₄haloalkyl), —C(O)—O—(C₁-C₄ alkyl), —C(O)—N(C₁-C₄ alkyl)₂, —C(O)—NH(C₁-C₄alkyl), —C(O)—(C₁-C₄ alkyl), oxetanyl, —C(O)-oxetanyl, —C(O)—O-oxetanyl,—CH₂-oxetanyl, tetrahydrofuranyl, or morpholinyl.

In some embodiments, R¹ is 8-azabicyclo[3.2.1]oct-2-ene-3-yl, wherein R¹is unsubstituted or substituted with C₁-C₄ alkyl, halo-substituted C₁-C₄alkyl, —C(O)—O—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl), or —C(O)-heteroaryl,and in any one or more of these embodiments, the

-   -   heteroaryl portion of an R¹ substituent is optionally        substituted.

In some embodiments, R¹ is cyclohexyl, wherein R¹ is substituted with—C(O)— heterocyclyl, or —COOH; and the heterocyclyl substituent isoptionally substituted with oxo, or C₁-C₄ alkyl.

In some embodiments, R¹ is methyl, 4-(morpholin-4-yl-sulfonyl)phenyl,4-(4-methylpiperazin-1-ylmethyl)phenyl, 4-fluorophenyl,1-methylpiperdin-4-yl, 4-(morpholin-4-ylcarbonyl)cyclohexyl,1-(morpholin-4-ylcarbonyl)cyclohex-3-en-4-yl,4-(piperidin-4-ylcarbonyl)piperazin-1-yl,4-(piperidin-4-ylcarbonyl)piperidin-1-yl, 4-dimethylaminopiperidin-1-yl,4-dimethylaminomethylpiperidin-1-yl, 3-dimethylaminopiperidin-1-yl,3-hydroxypiperidin-1-yl, pyrrolidin-3-yl, cyclopentyl,4-(dimethylaminomethylcarbonyl)piperazin-1-yl,4-(2-dimethylaminoethylcarbonyl)piperazin-1-yl,4-(oxetan-3-ylmethylcarbonyl)piperazin-1-yl, piperidin-4-yl,4-hydroxycarbonylpiperidin-1-yl, 5-methylsulfonylpyridin-3-yl,4-hydroxycarbonylcyclohex-1-ene-1-yl, 4-hydroxycarbonylcyclohexyl,4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 3,6-dihydro-2H-pyran-4-yl,tetrahydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl,4-(hydroxycarbonylmethyl)phenyl, or 4-(2H-tetrazol-5-yl)phenyl.

In some embodiments, R¹ is —CN, —CH₂CN,1-((1-oxetan-3-ylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(1-trifluoromethylcyclopropylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2,2-trifluoroethan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2,6-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(3,3,3-trifluoropropan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(azetidin-1-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(ethan-2-ylsulfonyl)-3-(cyanomethyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(hexahydro-1H-furo[3,4-c]pyrrol-5-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(isopropylaminocarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(pyrrolidin-1-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazol-4-yl,1-(1,3-dimethylpyrazol-5-yl)pyrazol-4-yl,1-(1-acetylazetidin-3-yl)pyrazol-4-yl,1-(1-acetylpyrrolidin-3-yl)pyrazol-4-yl,1-(1-cyanocyclopropylmethyl)pyrazol-4-yl,1-(1H-pyrazol-4-ylmethyl)pyrazol-4-yl,1-(1-hydroxy-3-chloropropan-2-yl)pyrazol-4-yl,1-(1-hydroxylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methoxycarbonylazetidin-3-yl)pyrazol-4-yl,1-(1-methyl-2(1H)-pyridinon-5-ylmethyl)pyrazol-4-yl,1-(1-methyl-2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(1-methylaminocarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl,1-(1-t-butoxycarbonylpyrrolidin-3-yl)pyrazol-4-yl,1-(2-(1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-1,3,4-oxadiazol-5-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3,5-dimethylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylazetidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxypyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-cyano-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4yl,1-(2-(4-hydroxy-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(morpholin-4-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-difluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(methyl)-2-(morpholin-4-yl)propan-3-yl)pyrazol-4-yl,1-(2-(methyl)-3-(morpholin-4-yl)propan-2-yl)pyrazol-4-yl,1-(2-(pyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-cyanoethyl)pyrazol-4-yl,1-(2-hydroxy-2-methylpropan-1-yl)pyrazol-4-yl,1-(2-methoxyethyl)pyrazol-4-yl,1-(2-methyl-3-hydroxypropan-2-yl)pyrazol-4-yl,1-(2-methylpropyl)pyrazol-4-yl, 1-(2-methylpyridin-4-yl)piperdin-3-yl,1-(2-methylpyrimidin-4-yl)pyrrolidin-3-yl,1-(2-methylsulfonylethan-1-yl)pyrazol-4-yl,1-(2-morpholin-4-ylethyl)pyrazol-4-yl,1-(2-oxopyrrolidin-3-yl)pyrazol-4-yl,1-(2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)pyrazol-4-yl,1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(4-methylpiperazin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(4-methylpyrimindin-2-yl)piperidin-4-yl,1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)pyrazol-4-yl,1-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)pyrazol-4-yl,1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(5-oxopyrrolidin-2-ylmethyl)pyrazol-4-yl,1-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)pyrazol-4-yl,1-(6-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(ethoxycarbonylmethyl)pyrazol-4-yl,1-(hexahydrofuro[2,3-b]furan-3-yl)pyrazol-4-yl,1-(hydroxycarbonylmethyl)pyrazol-4-yl,1-(isopropylaminocarbonylmethyl)pyrazol-4-yl,1-(isopropylcarbonylmethyl)pyrazol-4-yl,1-(methylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylmethyl)pyrazol-4-yl,1-(morpholin-4-ylcarbonylmethyl)pyrazol-4-yl,1-(oxetan-2-ylmethyl)pyrazol-4-yl, 1-(oxetan-3-ylmethyl)pyrazol-4-yl,1-(pyrazin-2-ylmethyl)pyrazol-4-yl,1-(pyridazin-4-ylmethyl)pyrazol-4-yl,1-(pyridin-3-ylmethyl)pyrazol-4-yl,1-(pyrrolidin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(t-butoxycarbonyl)3,6-dihydropyridin-4-yl,1-(t-butoxycarbonyl)piperidin-3-yl,1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl,1-(tetrahydrofuran-3-yl)pyrazol-4-yl,1-(tetrahydrofuran-3-ylaminocarbonylmethyl)pyrazol-4-yl,1-(tetrahydropyran-4-yl)pyrazol-4-yl,1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl, 1,3-dimethylpyrazol-4-yl,1-acetylpiperidin-3-yl, 1-acetylpyrrolidin-3-yl,1-difluoromethylpyrazol-4-yl, 1H-benzo[d]imidazol-6-yl, 1H-indol-5-yl,1H-indol-6-yl, 1H-pyrazol-4-yl, 1-methyl-1,2,3-triazol-4-yl,1-methylimidazol-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl,1-methylsulfonylpiperidin-3-yl, 1-methylsulfonylpyrrolidin-3-yl,1-oxetan-3-ylpyrazol-4-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-5-yl,1-t-butylpyrazol-4-yl, 2-(1, 1-dioxothiomorpholin-4-ylpyridin-4-yl,2-(1-methylpiperidin-3-yloxy)pyridin-4-yl,2-(1-methylpiperidin-4-yloxy)pyridin-4-yl,2-(1-methylpyrrolidin-3-yloxy)pyridin-4-yl,2-(2-methoxyethan-1-yloxy)pyridin-4-yl,2-(3-methoxypropan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f]-1,2,4-triazin-5-yl,2-(3-oxopiperazin-1-yl)pyridin-4-yl,2-(4-acetylpiperazin-1-yl)pyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl,2-(4-methylsulfonylpiperazin-1-yl)pyridin-4-yl,2-(morpholin-4-yl)pyridin-4-yl, 2-(oxetan-3-yloxy)pyridin-4-yl,2-(piperidin-3-yloxy)pyridin-4-yl, 2-(piperidin-4-yloxy)pyridin-4-yl,2-(pyrrolidin-3-yloxy)pyridin-4-yl, 2,6-dimethylpyridin-4-yl,2-hydroxycarbonylpyrimidin-5-yl, 2-isopropoxypyridin-4-yl,2-isopropylaminopyridin-4-yl,2-methyl-2-(morpholin-4-ylcarbonyl)but-3-yn-4-yl,2-methylaminocarbonyl-6-methylpyridin-4-yl,2-methylaminocarbonylpyridin-4-yl, 2-methylaminocarbonylpyrimidin-5-yl,2-methylaminopyridin-4-yl, 2-methyloxazol-5-yl, 2-methylpyridin-4-yl,2-morpholin-4-ylpyridin-4-yl, 2-oxoindolin-5-yl, 2-oxoindolin-6-yl,2-oxopyrrolidin-1-yl, 2-pyrrolidin-1-ylpyridin-4-yl,3-(1-pyrrolidin-1-ylethyl)phenyl,3-(3,3-difluoropyrrolidin-1-ylmethyl)phenyl,3-(3-fluoropyrrolidin-1-ylmethyl)phenyl,3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl, 3-(morpholin-4-yl)phenyl,3-(morpholin-4-ylmethyl)phenyl, 3-(pyrrolidin-1-ylmethyl)phenyl,3-fluoro-4-cyanophenyl, 3-methylisoxazol-4-yl, 3-methylpyridazin-5-yl,3-oxomorpholin-4-yl,4-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclopropyl)phenyl,4-(1-(1-methylpiperazin-4-yl)cyclopentyl)phenyl,4-(1-(hydroxycarbonyl)cyclopropyl)phenyl,4-(1-(morpholin-4-ylcarbonyl)cyclopropyl)phenyl,4-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclohexyl,4-(1,1-dioxothiomorpholin-4-ylcarbonyl)phenyl,4-(1-morpholin-4-ylcyclopentyl)phenyl, 4-(1-morpholin-4-ylethyl)phenyl,4-(1-pyrrolidin-1-ylethyl)phenyl,4-(2-oxa-6-azaspiro[3.3]hepatan-6-ylcarbonyl)cyclohexyl,4-(4-(4-methylpyrimidin-2-yl)piperazin-1-ylmethyl)phenyl,4-(4,4-difluoropiperdin-1-ylcarbonyl)cylohexyl,4-(4-acetylpiperazin-1-ylmethyl)phenyl,4-(4-methylpiperazin-1-ylcarbonyl)phenyl,4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl,4-(morpholin-4-ylcarbonyl)phenyl, 4-(morpholin-4-ylmethyl)phenyl,4-(pyrrolidin-1-ylcarbonyl)phenyl, 4-(pyrrolidin-1-ylmethyl)phenyl,4-hydroxycarbonylphenyl, 4-methylpyridin-2-yl, 4-methylpyridin-3-yl,5-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)thien-2-yl,5-(2-(morpholin-4-ylcarbonyl)propan-2-yl)thien-2-yl,5-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,5-(morpholin-4-ylcarbonyl)thien-3-yl,5-(morpholin-4-ylmethyl)pyridin-3-yl,5-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl,5-(S-imino(methyl)sulfinyl)pyridin-2-yl,5-(S-imino(methyl)sulfinyl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl,5-cyanopyridin-3-yl, 5-dimethylaminocarbonylpyridin-3-yl,5-fluoropyridin-3-yl, 5-hydroxycarbonylpyridin-3-yl,5-methylaminocarbonylpyridin-3-yl, 5-methylaminosulfonylpyridin-3-yl,5-methylpyridin-2-yl, 5-methylpyridin-3-yl,6-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-yl)pyridin-4-yl,6-(1-methylpiperazin-4-yl)pyridin-3-yl,6-(2-(2-hydroxypropan-2yl)morpholin-4-yl)pyridin-4-yl,6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-4-yl,6-(2-hydroxypropan-2-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-5-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-4-yl,6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(2-oxo-oxazol-3-yl)pyridin-4-yl,6-(3-methyl-3-hydroxyazetidin-1-yl)pyridin-4-yl,6-(3-methyl-3-hydroxypyrrolidin-1-yl)pyridin-4-yl,6-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(3-oxomorpholin-4-yl)pyridin-4-yl,6-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(N-isopropyl-N-ethylaminocarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylcarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-yloxycarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxtean-3-yl)piperazin-1-yl)pyridin-4-yl,6-(4-methoxycarbonylpiperazin-1-yl)pyridin-4-yl,6-(4-methyl-4-hydroxypiperidin-1-yl)pyridin-4-yl,6-(4-methylpiperaizin-1-ylmethyl)pyridin-4-yl,6-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,6-(4-trifluoromethylsulfonylpiperazin-1-yl)pyridin-4-yl,6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl,6-(hexahydro-1H-furo[3,4-c]pyrrol-5-yl)pyridin-4-yl,6-(isopropylaminocarbonyl)pyridin-3-yl,6-(methylaminocarbonyl)pyridin-3-yl, 6-(morpholin-4-yl)pyridin-4-yl,6-(morpholin-4-ylcarbonyl)pyridin-3-yl,6-(morpholin-4-ylmethyl)pyridin-3-yl, 6-(oxetan-3-yl)pyridin-4-yl,6-(piperazin-1-yl)pyridin-4-yl, 6-(pyridin-3-yloxy)pyridin-4-yl,6-(S-imino(methyl)sulfinyl)pyridin-4-yl,6-(S-methyl-S-iminosulfinyl)pyridin-3-yl,6-(tetrahydropyran-3-ylamino)pyridin-4-yl,6-(tetrahydropyran-4-ylamino)pyridin-4-yl, 6-fluoropyridin-4-yl,6-methylaminosulfonylpyridin-3-yl, 6-methylpyridin-2-yl,6-methylpyridin-3-yl, 6-methylpyridin-4-yl,6-methylsulfonylpyridin-3-yl, 6-methylsulfonylpyridin-4-yl,7-oxo-2-oxa-6-azaspiro[3.4]octan-6-yl,8-(1,1,1-trifluoroethan-2-yl)-8-azabicyclo[3.2.1]oct-2-en-3-yl,8-(acetyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl,8-(morpholin-4-yl-carbonyl)-8-azabicyclo[3.2.1]oct-6-en-7-yl,8-azabicyclo[3.2.1]oct-2-ene-3-yl,8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl,8-methyl-8-azabicyclo[3.2.1]octan-3-yl,8-t-butoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene-3-yl,8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl, benzo[d]oxazol-5-yl,benzo[d]oxazol-6-yl, imidazo[1,2-a]pyridin-6-yl, or piperdin-3-yl.

In some embodiments, R¹ is1-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(1-trifluoromethylcyclopropylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2,2-trifluoroethan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2,6-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(3,3,3-trifluoropropan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(azetidin-1-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(hexahydro-1H-furo[3,4-c]pyrrol-5-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(isopropylaminocarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(pyrrolidin-1-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazol-4-yl,1-(1,3-dimethylpyrazol-5-yl)pyrazol-4-yl,1-(1-acetylazetidin-3-yl)pyrazol-4-yl,1-(1-cyanocyclopropylmethyl)pyrazol-4-yl, 1-(1-ethylsulfonyl-3-cyanomethylazetidin-3-yl)pyrazol-4-yl,1-(1H-pyrazol-4-ylmethyl)pyrazol-4-yl,1-(1-hydroxylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methoxycarbonylazetidin-3-yl)pyrazol-4-yl,1-(1-methyl-2(1H)-pyridinon-5-ylmethyl)pyrazol-4-yl,1-(1-methyl-2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(1-methylaminocarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl,1-(1-morpholin-4-ylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-t-butoxycarbonylpyrrolidin-3-yl)pyrazol-4-yl,1-(2-(1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-1,3,4-oxadiazol-5-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3,5-dimethylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylazetidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxypyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-cyano-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4yl,1-(2-(4-hydroxy-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-difluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(methyl)-2-(morpholin-4-yl)propan-3-yl)pyrazol-4-yl,1-(2-(methyl)-3-(morpholin-4-yl)propan-2-yl)pyrazol-4-yl,1-(2-(morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-cyanoethyl)pyrazol-4-yl, 1-(2-methoxyethyl)pyrazol-4-yl,1-(2-methylsulfonylethan-1-yl)pyrazol-4-yl,1-(2-morpholin-4-ylethyl)pyrazol-4-yl,1-(2-oxopyrrolidin-3-yl)pyrazol-4-yl,1-(2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)pyrazol-4-yl,1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)pyrazol-4-yl,1-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)pyrazol-4-yl,1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(5-oxopyrrolidin-2-ylmethyl)pyrazol-4-yl,1-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)pyrazol-4-yl,1-(6-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(ethoxycarbonylmethyl)pyrazol-4-yl,1-(hexahydrofuro[2,3-b]furan-3-yl)pyrazol-4-yl,1-(hydroxycarbonylmethyl)pyrazol-4-yl,1-(isopropylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylaminocarbonylmethyl)-pyrazol-4-yl,1-(methylsulfonylmethyl)pyrazol-4-yl,1-(morpholin-4-ylcarbonyl)cyclohex-3-en-4-yl,1-(morpholin-4-ylcarbonylmethyl)pyrazol-4-yl,1-(oxetan-2-ylmethyl)pyrazol-4-yl, 1-(oxetan-3-ylmethyl)pyrazol-4-yl,1-(pyrazin-2-ylmethyl)pyrazol-4-yl,1-(pyridazin-4-ylmethyl)pyrazol-4-yl,1-(pyridin-3-ylmethyl)pyrazol-4-yl,1-(pyrrolidin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(t-butoxycarbonyl)3,6-dihydropyridin-4-yl,1-(tetrahydrofuran-3-yl)pyrazol-4-yl,1-(tetrahydrofuran-3-ylaminocarbonylmethyl)pyrazol-4-yl,1,2,3,6-tetrahydropyridin-4-yl, 1-difluoromethylpyrazol-4-yl,1H-benzo[d]imidazol-6-yl, 1H-indol-6-yl, 1H-pyrazol-4-yl,1-methylpyrazol-4-yl, 1-oxetan-3-ylpyrazol-4-yl, 1-t-butylpyrazol-4-yl,2-(1,1-dioxothiomorpholin-4-ylpyridin-4-yl,2-(1-methylpiperidin-3-yloxy)pyridin-4-yl,2-(1-methylpiperidin-4-yloxy)pyridin-4-yl,2-(2-methoxyethan-1-yloxy)pyridin-4-yl,2-(3-oxopiperazin-1-yl)pyridin-4-yl,2-(4-acetylpiperazin-1-yl)pyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl,2-(4-methylsulfonylpiperazin-1-yl)pyridin-4-yl,2-(morpholin-4-yl)pyridin-4-yl, 2-(oxetan-3-yloxy)pyridin-4-yl,2-hydroxycarbonylpyrimidin-5-yl, 2-isopropoxypyridin-4-yl, 2isopropylaminopyridin-4-yl, 2-methylaminocarbonyl-6-methylpyridin-4-yl,2-methylaminocarbonylpyridin-4-yl, 2-methylaminocarbonylpyrimidin-5-yl,2-methylaminopyridin-4-yl, 2-methylpyridin-4-yl,2-morpholin-4-ylpyridin-4-yl, 2-pyrrolidin-1-ylpyridin-4-yl,3-(1-pyrrolidin-1-ylethyl)phenyl,3-(3-fluoropyrrolidin-1-ylmethyl)phenyl,3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl, 3-(morpholin-4-yl)phenyl,3,6-dihydro-2H-pyran-4-yl, 3-methylisoxazol-4-yl,4-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclopropyl)phenyl,4-(1-morpholin-4-ylethyl)phenyl, 4-(1-pyrrolidin-1-ylethyl)phenyl,4-(2H-tetrazol-5-yl)phenyl,4-(4,4-difluoropiperdin-1-ylcarbonyl)cylohexyl,4-(4-acetylpiperazin-1-ylmethyl)phenyl,4-(4-methylpiperazin-1-ylcarbonyl)phenyl,4-(4-methylpiperazin-1-ylmethyl)phenyl,4-(4-methylpiperazin-1-ylmethyl)phenyl,4-(morpholin-4-ylcarbonyl)cyclohexyl, 4-(morpholin-4-ylmethyl)phenyl,4-(morpholin-4-ylsulfonyl)phenyl, 4-(pyrrolidin-1-ylcarbonyl)phenyl,4-(pyrrolidin-1-ylmethyl)phenyl, 4-hydroxycarbonylcyclohex-1-ene-1-yl,5-(2-(morpholin-4-ylcarbonyl)propan-2-yl)thien-2-yl,5-(morpholin-4-ylcarbonyl)pyridin-3-yl,5-(morpholin-4-ylcarbonyl)thien-3-yl,5-dimethylaminocarbonylpyridin-3-yl, 5-hydroxycarbonylpyridin-3-yl,5-methylaminocarbonylpyridin-3-yl, 5-methylaminosulfonylpyridin-3-yl,5-methylsulfonylpyridin-3-yl,6-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-yl)pyridin-4-yl,6-(2-(2-hydroxypropan-2-yl)morpholin-4-yl)pyridin-4-yl,6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-4-yl,6-(2-hydroxypropan-2-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-5-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-4-yl,6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(2-oxo-oxazol-3-yl)pyridin-4-yl,6-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(3-oxomorpholin-4-yl)pyridin-4-yl,6-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(N-isopropyl-N-ethylaminocarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-yloxycarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxtean-3-yl)piperazin-1-yl)pyridin-4-yl,6-(4-methoxycarbonylpiperazin-1-yl)pyridin-4-yl,6-(4-methyl-4-hydroxypiperidin-1-yl)pyridin-4-yl,6-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,6-(4-methylpiperazin-1-ylmethyl)pyridin-4-yl,6-(4-trifluoromethylsulfonylpiperazin-1-yl)pyridin-4-yl,6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl,6-(hexahydro-1H-furo[3,4-c]pyrrol-5-yl)pyridin-4-yl,6-(methylaminocarbonyl)pyridin-3-yl, 6-(morpholin-4-yl)pyridin-4-yl,6-(morpholin-4-ylcarbonyl)pyridin-3-yl, 6-(oxetan-3-yl)pyridin-4-yl,6-(piperazin-1-yl)pyridin-4-yl, 6-(pyridin-3-yloxy)pyridin-4-yl,6-(S-imino(methyl)sulfinyl)pyridin-4-yl,6-(S-methyl-S-iminosulfinyl)pyridin-3-yl,6-(tetrahydropyran-3-ylamino)pyridin-4-yl,6-(tetrahydropyran-4-ylamino)pyridin-4-yl, 6-fluoropyridin-4-yl,6-methylaminosulfonylpyridin-3-yl, 6-methylpyridin-3-yl,6-methylsulfonylpyridin-3-yl, 6-trifluoromethylpyridin-4-yl,8-(1,1,1-trifluoroethan-2-yl)-8-azabicyclo[3.2.1]oct-2-en-3-yl,8-(acetyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl,8-(morpholin-4-yl-carbonyl)-8-azabicyclo[3.2.1]oct-6-en-7-yl,8-azabicyclo[3.2.1]oct-2-ene-3-yl,8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl, benzo[d]oxazol-5-yl,benzo[d]oxazol-6-yl, or imidazo[1,2-a]pyridin-6-yl.

In some embodiments, L² is a bond.

In some embodiments, R² is optionally substituted heterocyclyl. In someof these embodiments, R² is an optionally substituted tetrahydropyranyl,piperidinyl, hexahydrothiopyranyl, or tetrahydroindazolyl. In someaspects of these embodiments, R² is a heterocyclyl optionallysubstituted with one or more substituent selected from oxo, hydroxyl,fluoro, methoxy, methyl, amino, imino, methylamino and dimethylamino. Insome aspects of these embodiments, R² is tetrahydropyran-4-yl,1-oxohexahydrothiopyran-4-yl, 1-imino-1-oxohexahydrothiopyran-4-yl,2-oxopiperdin-4-yl, 2-oxopiperdin-5-yl, hexahydrothiopyran-4-yl,4,5,6,7-tetrahydro-1H-indazol-4-yl or4,5,6,7-tetrahydro-1H-indazol-5-yl.

In some embodiments, R² is optionally substituted aryl or heteroaryl. Insome aspects of these embodiments, R² is an optionally substitutedpyridinyl or phenyl. In some aspects of these embodiments, R² is2-hydroxypyridin-4-yl or 4-methoxyphenyl.

In some embodiments, R² is optionally substituted C₃-C₈ cycloalkyl. Insome aspects of these embodiments, R² is an optionally substitutedcyclohexyl. In some aspects of these embodiments, R² is a substitutedcyclohexyl. In some aspects of these embodiments, R² is a substitutedcyclohexyl, wherein two substituents on the same ring carbon atom aretaken together to form an optionally substituted heterocyclic ring thatis spiro fused to the cyclohexyl. In some aspects of these embodiments,R² is an optionally substituted cyclopentyl.

In some embodiments, R² is 4-hydroxycyclohexyl or4-methyl-4-hydroxycyclohexyl.

In some embodiments, R² is 4-methoxycyclohexyl, 4-aminocyclohexyl,4-methylcarbonylaminocyclohexyl, 4-methylsylfonylaminocyclohexyl,4-(1,2-dioxo-4-methylaminocyclobut-3-enylamino)cyclohexyl,4-(2-cyano-3-methylguanidinyl)cyclohexyl,2,4-dioxo-1,3-diazaspiro[4.5]decan-8-yl, 4-oxocyclohexyl,3-hydroxycyclopentyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl,3,3-dimethyl-4-hydroxycyclohexyl, 3,3-difluoro-4-hydroxycyclohexyl,3-methyl-4-hydroxycyclohexyl, 4-isopropyl-4-hydroxycyclohexyl,4-ethyl-4-hydroxycyclohexyl, or 4-dimethylaminocyclohexyl.

In some embodiments, R² is 4-hydroxycyclohexyl,4-methylcarbonylaminocyclohexyl, 4-methylsylfonylaminocyclohexyl,4-(1,2-dioxo-4-methylaminocyclobut-3-enylamino)cyclohexyl,4-(2-cyano-3-methylguanidinyl)cyclohexyl,2,4-dioxo-1,3-diazaspiro[4.5]decan-8-yl, 3-methyl-4-hydroxycyclohexyl,4-fluorocyclohexyl, 4-isopropyl-4-hydroxycyclohexyl,4-ethyl-4-hydroxycyclohexyl, or 4,5,6,7-tetrahydro-1H-indazol-5-yl.

In some embodiments, R³ is —C₃-C₈ alkyl, —(C₂-C₆ alkylene)-O—(C₁-C₆alkyl), phenyl, C₃-C₆ cycloalkyl, or saturated heterocyclyl, whereineach R³ is optionally substituted with 1-2 substituents independentlyselected from halo, —OH, —C₁-C₄ alkyl, and —O—C₁-C₄ alkyl.

In some embodiments, R³ is —C₃-C₈ alkyl, —(C₂-C₆ alkylene)-O—(C₁-C₆alkyl), C₃-C₆ cycloalkyl, —(C₂-C₆ alkylene)-C₃-C₆ cycloalkyl, —(C₂-C₆alkylene)-saturated heterocyclyl, or saturated heterocyclyl, whereineach R³ is optionally substituted with 1-5 substituents independentlyselected from deuterium, halo, —OH, —CN, —C₁-C₄ alkyl, —(C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —O—C₁-C₄ alkyl, —N(C₁-C₄ alkyl)₂.

In some embodiments, R³ is n-butyl, isopropyl, butan-2-yl, heptan-2-yl,1,3-dimethoxypropan-2-yl, 3-methoxypropan-2-yl, pentan-2-yl,4-methylpentan-2-yl, pentan-3-yl, cyclopentyl, 4-chlorophenyl,tetrahydrofuran-3-yl, 3-hydroxypropan-2-yl, 3,3-dimethylcyclobutyl,2,2-dimethylcyclobutyl, or 1-ethylcyclobutyl.

In some embodiments, R³ is 1-(methoxymethyl)cyclopropanyl,3,3-(difluoromethoxy)propan-2-yl, 3-(tetrahydrofuran-2-yl)propan-2-yl,3,3,3-trifluoropropan-2-yl, 3,3-difluoropropan-2-yl, 3-cyanopropan-2-yl,3-cyclopropylpropan-2-yl, 3-ethoxypropan-2-yl,4,4,4-trifluorobutan-2-yl, 4-fluorobutan-2-yl, 4-methoxybutan-2-yl,4-difluoromethoxybutan-2-yl, 4,4-difluorobutan-2-yl,2-methoxyethan-1-yl, 2-cyclopropanylethan-1-yl,3,3,3-trifluoropropan-1-yl, 3-dimethylaminopropan-2-yl,1-methyltetrahydrofuran-3-yl, 2-(oxetan-3-yl)ethan-2-yl,3-(oxetan-3-yl)propan-2-yl, 2-(pyridin-2-yl)ethan-2-yl,2-(pyridin-3-yl)ethan-2-yl, 2-(pyridin-4-yl)ethan-2-yl,2-(phenyl)ethan-2-yl, 3-(4-fluorophenyl)propan-2-yl,3-tridueteromethoxypropan-2-yl, or 3-(phenoxy)propan-2-yl.

In some embodiments, R³ is isopropyl, n-butanyl, heptan-2-yl,propan-2-yl, 3-methoxypropan-2-yl, 3,3-(difluoromethoxy)propan-2-yl,3,3-difluoropropan-2-yl, 3-cyclopropylpropan-2-yl,4,4,4-trifluorobutan-2-yl, 4-fluorobutan-2-yl, 4,4-difluorobutan-2-yl,2-methoxyethan-1-yl, 2-cyclopropanylethan-1-yl, or3,3,3-trifluoropropan-1-yl.

In some embodiments, R⁴ is hydrogen.

In some embodiments, both L¹ and L² are bonds; R⁴ and R⁵ are hydrogen,and the compound has structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², and R³are as defined for Formula I, including the specific listings ofmoieties for each of those variables set forth above.

In some embodiments of Formula II, R¹ is pyridin-3-yl, pyridin-4-yl,pyrazol-4-yl, cyclohexyl, or 8-azabicyclo[3.2.1]oct-2-ene-3-yl, whereinR¹ is optionally substituted with up to four independently selectedsubstituents. In some compound of this embodiment, R¹ is optionallysubstituted with up to four substituents independently selected fromhalo, hydroxy, —CN, —(C₁-C₄ alkyl optionally substituted with one ormore substituents selected from cyano, hydroxy and halo), —C(O)NH₂,—COOH, —(C₀-C₃ alkylene)-C(O)—(C₁-C₄ alkyl), —(C₀-C₃alkylene)-C(O)—NH—(C₁-C₄ alkyl), —(C₀-C₃ alkylene)-C(O)—NH—S(O)₂—(C₁-C₄alkyl), —(C₀-C₃ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₃ alkylene)-COOH,—(C₀-C₄ alkylene)-S(O)₂—(C₁-C₃ alkyl), —(C₁-C₃ alkylene)-O—(C₁-C₄alkyl), —S(O)(═NH)—(C₁-C₄ alkyl), —S(O)₂—NH—(C₁-C₄ alkyl),-(cyclopropyl)-(cyano-substituted C₁-C₃ alkyl),-(cyclopropyl)-C(O)—NH—(C₁-C₄ alkyl), —(C₀-C₃alkylene)-C(O)-heterocyclyl, —C(O)—(C₀-C₃ alkylene)-heterocyclyl,-(cyclopropyl)-C(O)-heterocyclyl, —(C₀-C₄ alkylene)-heterocyclyl,—(C₀-C₃ alkylene)-C(O)—NH-heterocyclyl, —(C₀-C₄ alkylene)-aryl, and—(C₀-C₄ alkylene)-heteroaryl, wherein the heterocyclyl or heteroarylportion of the R¹ substitutent is optionally further substituted.

In some embodiments of Formula II, R¹ is1-((1-oxetan-3-ylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(1-trifluoromethylcyclopropylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2,2-trifluoroethan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2,6-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(3,3,3-trifluoropropan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(azetidin-1-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(ethan-2-ylsulfonyl)-3-(cyanomethyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(hexahydro-1H-furo[3,4-c]pyrrol-5-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(isopropylaminocarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(pyrrolidin-1-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazol-4-yl,1-(1,3-dimethylpyrazol-5-yl)pyrazol-4-yl,1-(1-acetylazetidin-3-yl)pyrazol-4-yl,1-(1-acetylpyrrolidin-3-yl)pyrazol-4-yl,1-(1-cyanocyclopropylmethyl)pyrazol-4-yl,1-(1H-pyrazol-4-ylmethyl)pyrazol-4-yl,1-(1-hydroxy-3-chloropropan-2-yl)pyrazol-4-yl,1-(1-hydroxylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methoxycarbonylazetidin-3-yl)pyrazol-4-yl,1-(1-methyl-2(1H)-pyridinon-5-ylmethyl)pyrazol-4-yl,1-(1-methyl-2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(1-methylaminocarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl,1-(1-t-butoxycarbonylpyrrolidin-3-yl)pyrazol-4-yl,1-(2-(1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-1,3,4-oxadiazol-5-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3,5-dimethylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylazetidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxypyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-cyano-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4yl,1-(2-(4-hydroxy-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(morpholin-4-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-difluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(methyl)-2-(morpholin-4-yl)propan-3-yl)pyrazol-4-yl,1-(2-(methyl)-3-(morpholin-4-yl)propan-2-yl)pyrazol-4-yl,1-(2-(pyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-cyanoethyl)pyrazol-4-yl,1-(2-hydroxy-2-methylpropan-1-yl)pyrazol-4-yl,1-(2-methoxyethyl)pyrazol-4-yl,1-(2-methyl-3-hydroxypropan-2-yl)pyrazol-4-yl,1-(2-methylpropyl)pyrazol-4-yl,1-(2-methylsulfonylethan-1-yl)pyrazol-4-yl,1-(2-morpholin-4-ylethyl)pyrazol-4-yl,1-(2-oxopyrrolidin-3-yl)pyrazol-4-yl,1-(2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)pyrazol-4-yl,1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(4-methylpiperazin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)pyrazol-4-yl,1-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)pyrazol-4-yl,1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(5-oxopyrrolidin-2-ylmethyl)pyrazol-4-yl,1-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)pyrazol-4-yl,1-(6-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(ethoxycarbonylmethyl)pyrazol-4-yl,1-(hexahydrofuro[2,3-b]furan-3-yl)pyrazol-4-yl,1-(hydroxycarbonylmethyl)pyrazol-4-yl,1-(isopropylaminocarbonylmethyl)pyrazol-4-yl,1-(isopropylcarbonylmethyl)pyrazol-4-yl,1-(methylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylmethyl)pyrazol-4-yl,1-(morpholin-4-ylcarbonylmethyl)pyrazol-4-yl,1-(oxetan-2-ylmethyl)pyrazol-4-yl, 1-(oxetan-3-ylmethyl)pyrazol-4-yl,1-(pyrazin-2-ylmethyl)pyrazol-4-yl,1-(pyridazin-4-ylmethyl)pyrazol-4-yl,1-(pyridin-3-ylmethyl)pyrazol-4-yl,1-(pyrrolidin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl,1-(tetrahydrofuran-3-yl)pyrazol-4-yl,1-(tetrahydrofuran-3-ylaminocarbonylmethyl)pyrazol-4-yl,1-(tetrahydropyran-4-yl)pyrazol-4-yl,1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl, 1,3-dimethylpyrazol-4-yl,1-difluoromethylpyrazol-4-yl, 1H-pyrazol-4-yl, 1-methylpyrazol-3-yl,1-methylpyrazol-4-yl, 1-oxetan-3-ylpyrazol-4-yl, 1-t-butylpyrazol-4-yl,2-(1,1-dioxothiomorpholin-4-yl)pyridin-4-yl,2-(1-methylpiperidin-3-yloxy)pyridin-4-yl,2-(1-methylpiperidin-4-yloxy)pyridin-4-yl,2-(1-methylpyrrolidin-3-yloxy)pyridin-4-yl,2-(2-methoxyethan-1-yloxy)pyridin-4-yl,2-(3-oxopiperazin-1-yl)pyridin-4-yl,2-(4-acetylpiperazin-1-yl)pyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl,2-(4-methylsulfonylpiperazin-1-yl)pyridin-4-yl,2-(morpholin-4-yl)pyridin-4-yl, 2-(oxetan-3-yloxy)pyridin-4-yl,2-(piperidin-3-yloxy)pyridin-4-yl, 2-(piperidin-4-yloxy)pyridin-4-yl,2-(pyrrolidin-3-yloxy)pyridin-4-yl, 2,6-dimethylpyridin-4-yl,2-isopropoxypyridin-4-yl, 2 isopropylaminopyridin-4-yl,2-methylaminocarbonyl-6-methylpyridin-4-yl,2-methylaminocarbonylpyridin-4-yl, 2-methylaminopyridin-4-yl,2-methylpyridin-4-yl, 2-morpholin-4-ylpyridin-4-yl,2-pyrrolidin-1-ylpyridin-4-yl,4-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclohexyl,4-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)cyclohexyl,4-(4,4-difluoropiperidin-1-ylcarbonyl)cyclohexyl,4-(4-methylpiperazin-1-yl)carbonylcyclohexyl,4-(morpholin-4-ylcarbonyl)cyclohexyl, 4-hydroxycarbonylcyclohexyl,4-methylpyridin-3-yl, 5-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,5-(morpholin-4-ylmethyl)pyridin-3-yl,5-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl,5-(S-imino(methyl)sulfinyl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl,5-cyanopyridin-3-yl, 5-dimethylaminocarbonylpyridin-3-yl,5-fluoropyridin-3-yl, 5-hydroxycarbonylpyridin-3-yl,5-methylaminocarbonylpyridin-3-yl, 5-methylaminosulfonylpyridin-3-yl,5-methylpyridin-3-yl, 5-methylsulfonylpyridin-3-yl, 6-(1-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-yl)pyridin-4-yl,6-(1-methylpiperazin-4-yl)pyridin-3-yl,6-(2-(2-hydroxypropan-2yl)morpholin-4-yl)pyridin-4-yl,6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-4-yl,6-(2-hydroxypropan-2-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-5-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-4-yl,6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(2-oxo-oxazol-3-yl)pyridin-4-yl,6-(3-methyl-3-hydroxyazetidin-1-yl)pyridin-4-yl,6-(3-methyl-3-hydroxypyrrolidin-1-yl)pyridin-4-yl,6-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(3-oxomorpholin-4-yl)pyridin-4-yl,6-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(N-isopropyl-N-ethylaminocarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylcarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-yloxycarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-methoxycarbonylpiperazin-1-yl)pyridin-4-yl,6-(4-methyl-4-hydroxypiperidin-1-yl)pyridin-4-yl,6-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,6-(4-methylpiperazin-1-ylmethyl)pyridin-4-yl,6-(4-trifluoromethylsulfonylpiperazin-1-yl)pyridin-4-yl,6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl,6-(hexahydro-1H-furo[3,4-c]pyrrol-5-yl)pyridin-4-yl,6-(isopropylaminocarbonyl)pyridin-3-yl,6-(methylaminocarbonyl)pyridin-3-yl, 6-(morpholin-4-yl)pyridin-4-yl,6-(morpholin-4-ylcarbonyl)pyridin-3-yl,6-(morpholin-4-ylmethyl)pyridin-3-yl, 6-(oxetan-3-yl)pyridin-4-yl,6-(piperazin-1-yl)pyridin-4-yl, 6-(pyridin-3-yloxy)pyridin-4-yl,6-(S-imino(methyl)sulfinyl)pyridin-4-yl,6-(S-methyl-S-iminosulfinyl)pyridin-3-yl,6-(tetrahydropyran-3-ylamino)pyridin-4-yl,6-(tetrahydropyran-4-ylamino)pyridin-4-yl, 6-fluoropyridin-4-yl,6-methylaminosulfonylpyridin-3-yl, 6-methylpyridin-3-yl,6-methylpyridin-4-yl, or 6-methylsulfonylpyridin-3-yl.

In some embodiments of Formula II, R² is cyclohexyl substituted withhydroxy and optionally additionally substituted with one to threesubstituents independently selected from the group consisting of C₁-C₄alkyl and fluoro, or is 4,5,6,7-tetrahydro-1H-indazolyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁-C₄ alkyl and fluoro. In some compound ofthese embodiments, R² is 4-hydroxycyclohexyl,4-methyl-4-hydroxycyclohexyl, 3,3-difluoro-4-hydroxycyclohexyl,3-fluoro-4-hydroxycyclohexyl, or 4,5,6,7-tetrahydro-1H-indazolyl.

In some embodiments of Formula II, R³ is —C₃-C₈ alkyl, —(C₂-C₆alkylene)-O—(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, or —(C₂-C₆ alkylene)-C₃-C₆cycloalkyl, wherein R³ is optionally substituted with 1-5 substituentsindependently selected from the group consisting of deuterium, halo, and—OH.

In some embodiments, the compound has structural Formula III:

or a pharmaceutically acceptable salt thereof, wherein R¹ is as definedfor Formula I, including the specific listings of moieties for thatvariable set forth above.

In some embodiments, the compound of Formula III has the stereochemistrydepicted in Formula IIIa:

or is a pharmaceutically acceptable salt thereof, wherein R¹ is asdefined for Formula I, including the specific moieties for that variableset forth above.

In some embodiments, the compound of Formula III has the stereochemistrydepicted in Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein R¹ is as definedfor Formula I, including the specific moieties for that variable setforth above.

In some embodiments, the compound has structural Formula IV:

wherein:

R⁸ is —(C₀-C₄ alkylene)-S(O)₂—(C₁-C₃ alkyl), —C(O)—NH—(C₁-C₄ alkyl),—C₁-C₄ alkyl optionally substituted with one or more of halo, hydroxyand cyano, —NH—(C₁-C₄ alkyl), —O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl), —S(O)(═NH)—(C₁-C₄ alkyl), —S(O)₂—NH—(C₁-C₄ alkyl),—(C₀-C₃ alkylene)-C(O)-heterocyclyl, —(C₀-C₃ alkylene)-NH-heterocyclyl,—(C₀-C₄ alkylene)-heterocyclyl, —O-heteroaryl, or —O-heterocyclyl,wherein any heterocyclyl, or heteroaryl portion of R⁸ is optionallyfurther substituted;

R⁷ is —O—C₁-C₃ alkyl, C₁-C₃ haloalkyl, or —O—C₁-C₃ haloalkyl; and

R¹² is hydrogen, or C₁-C₄ alkyl; and

each of R^(13a) and R^(13b) is independently selected from hydrogen andfluoro.

In some embodiments of Formulae IV or V, R⁸ is —CH₃, —C(O)NHCH₃,—C(O)NHCH(CH₃)₂, —NHCH(CH₃)₂, —NHCH₃, —S(═O)(═NH)—CH₃, —S(═O)₂—CH₃,—S(═O)₂—NH—CH₃, 1,1-dioxothiomorpholin-4-yl,1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl,1-methylpiperidin-3-yloxy, 1-methylpiperidin-4-yloxy,1-methylpyrrolidin-3-yloxy, 1-oxa-7-azospiro[3.5]nonan-7-yl,2-(2-hydroxypropan-2-yl)morpholin-4-yl,2,5-dioxa-8-azospiro[3.5]nonan-8-yl, 2-methoxyethan-1-yloxy,2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl,2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl,2-oxa-6-azospiro[3.3]heptan-6-yl, 2-oxa-6-azospiro[3.5]octan-6-yl,2-oxa-7-azospiro[3.5]nonan-7-yl, 2-oxo-oxazolidin-3-yl,3-oxomorpholin-4-yl, 3-oxopiperazin-1-yl,4-(N-ethyl-N-isopropylaminocarbonyl)piperazin-1-yl,4-(oxetan-3-yl)piperazin-1-yl, 4-(oxetan-3-ylmethyl)piperazin-1-yl,4-acetylpiperazin-1-yl, 4-cyclopropylsulfonylpiperazin-1-yl,4-methoxycarbonylpiperazin-1-yl, 4-methylpiperazin-1-yl,4-methylpiperazin-1-ylmethyl, 4-sulfonylmethylpiperazin-1-yl,4-trifluoromethylsulfonylpiperazin-1-yl,8-oxa-3-azabicyclo[3.2.1]octan-3-yl, isopropyloxy, morpholin-4-carbonyl,morpholin-4-yl, morpholin-4-ylmethyl, oxetan-3-yl, oxetan-3-yloxy,piperazin-1-yl, piperidin-3-yloxy, piperidin-4-yloxy, pyridin-3-yloxy,pyrrolidin-1-yl, pyrrolidin-3-yloxy,tetrahydro-1H-furo[3,4-c]pyrrol-5-yl, tetrahydrofuran-3-ylamino, ortetrahydropyran-4-yl.

In some embodiments of Formulae IV or V, R⁸ is optionally substitutedmorpholin-4-yl, —S(═O)(═NH)—C₁-C₃ alkyl, or —S(═O)₂—C₁-C₃ alkyl. In somemore specific aspects of these embodiments, R⁸ is morpholin-4-yl,—S(═O)(═NH)—CH₃, or —S(═O)₂—CH₃.

In some embodiments of Formulae IV or V, R⁷ is —OCH₃, —CF₃, or —OCHF₂.

In some embodiments of Formulae IV or V, R¹² is hydrogen or —CH₃. Insome aspects of these embodiments, R¹² is hydrogen and each of R^(13a)and R^(13b) is fluoro. In some aspects of these embodiments, each of R¹²and R^(13a) is hydrogen and R^(13b) is fluoro. In some aspects of theseembodiments, each of R¹², R^(13a) and R^(13b) is hydrogen and thecompound has structural formula IVa:

or structural formula Va:

In some embodiments, the compound has structural Formula VI:

wherein:

R⁷ is —O—C₁-C₃ alkyl, C₁-C₃ haloalkyl, or —O—C₁-C₃ haloalkyl;

-   -   each of R^(9a) and R^(9b) are —CH₃, or R^(9a) and R^(9b) are        taken together with the carbon atom to which they are bound to        form cyclopropyl;

R⁹ is C₁-C₃ alkyl, C₁-C₃ hydroxyalkyl, —COOH, —C(O)NH—C₁-C₄ alkyl,—CH₂-heterocyclyl, —C(═O)-heterocyclyl or a 5-membered heteroaryl,wherein the heterocyclyl or heteroaryl portion of R⁹ is optionallysubstituted with up to two substituents independently selected from oxo,cyclopropyl, —OH, —CN, —C₁-C₃ alkyl, and —C₁-C₃ hydroxyalkyl; and

R¹² is hydrogen, or C₁-C₄ alkyl; and

each of R^(13a) and R^(13b) is independently selected from hydrogen andfluoro.

In some embodiments of Formula VI, R⁷ is —OCH₃, —CF₃, or —OCHF₂.

In some embodiment of Formula VI, R⁹ is —CH₃, —CH₂OH, —COOH, —C(O)NHCH₃,—C(O)NHCH(CH₃)₂, 1,1-dioxothiomorpholin-4-ylcarbonyl,2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl,2,2-dimethylmorpholin-4-ylcarbonyl,2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl,2,6-dimethylmorpholin-4-ylcarbonyl,2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl,2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl,3-hydroxpyrrolidin-1-ylcarbonyl, 4-cyano-4-methylpiperidin-1-ylcarbonyl,4-hydroxy-4-methylpiperidin-1-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-oxadiazol-2-yl,8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl, azetidin-1-ylcarbonyl,morpholin-4-ylcarbonyl, morpholin-4-ylmethyl, pyrrolidin-1-ylcarbonyl,or tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylcarbonyl. In some aspects ofthese embodiments, R⁹ is morpholin-4-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl,2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl,3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl.

In some embodiments of Formula VI, R¹² is hydrogen or —CH₃. In someaspects of these embodiments, R¹² is hydrogen and each of R^(13a) andR^(13b) is fluoro. In some aspects of these embodiments, each of R¹² andR^(13a) is hydrogen and R^(13b) is fluoro. In some aspects of theseembodiments, each of R¹², R^(13a) and R^(13b) is hydrogen and thecompound has structural formula VIa:

In some embodiments, the compound has structural Formula VII:

wherein:

R^(7a) is C₁-C₄ alkyl, —O—C₁-C₃ alkyl, C₁-C₃ haloalkyl, or —O—C₁-C₃haloalkyl;

R⁹ is —COOH, —C(═O)-heterocyclyl or a 5-membered heteroaryl, wherein R⁹is optionally substituted with up to two substituents independentlyselected from oxo, —OH and —C₁-C₃ alkyl; and

R¹² is hydrogen or C₁-C₄ alkyl; and

each of R^(13a) and R^(13b) are independently selected from hydrogen andfluoro.

In some embodiments of Formula VII, R^(7a) is —(CH₂)₃CH₃, —OCH₃, —CF₃,or —OCHF₂.

In some aspects of these embodiments, R^(7a) is —(CH₂)₃CH₃, —OCH₃, or—CF₃.

In some embodiments of Formula VII, R⁹ is —COOH, morpholin-4-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl,2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl,3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, or1,1-dioxothiomorpholin-4-ylcarbonyl. In some aspects of theseembodiments, R⁹ is —COOH, morpholin-4-ylcarbonyl, or1,1-dioxothiomorpholin-4-ylcarbonyl. In some more specific aspects ofthese embodiments, R⁹ is morpholin-4-ylcarbonyl.

In some embodiments of Formula VII, R¹² is hydrogen or —CH₃. In someaspects of these embodiments, R¹² is hydrogen and each of R^(13a) andR^(13b) is fluoro. In some aspects of these embodiments, each of R¹² andR^(13a) is hydrogen and R^(13b) is fluoro. In some aspects of theseembodiments, each of R¹², R^(13a) and R^(13b) is hydrogen and thecompound has structural formula VIIa:

In other embodiments, this disclosure provides a composition (e.g., apharmaceutical composition) comprising any of the compounds (as definedherein) described herein.

In some embodiments, a provided compound is a compound depicted in FIG.1, a pharmaceutically acceptable salt thereof, or other form thereof(e.g., as also described herein).

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Other pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

For ease of reading, we will not refer to both a compound of theinvention and a pharmaceutically acceptable salt thereof when describingeach and every composition, method, and use within the scope of theinvention. It is to be understood that where a compound of the inventioncan be used, a pharmaceutically acceptable salt thereof may also beuseful, and making that determination is well within the ability of oneof ordinary skill in the art. For example, a compound described hereinor a pharmaceutically acceptable salt thereof may have an increasedspecificity for at least one TAM kinase relative to another; may exhibitthat specificity relative to FLT3; and so forth as described herein.

In the unlikely event a compound described herein is found in nature,that compound may be provided and/or utilized as described herein in aform different from that in which it is found in nature. For example, acompound described herein can be provided or utilized as a non-naturallyoccurring racemic mixture or in a non-naturally occurring isotopic form.A composition of the invention (e.g., a pharmaceutical composition) cancontain a different concentration of a given compound (either a higheror lower concentration) than a reference composition or source (e.g., anatural source) of the compound and would, therefore, be a non-naturallyoccurring composition. For example, in some embodiments, a compound is“substantially pure” by virtue of being substantially free of other,distinct chemical compounds, including but not limited to those withwhich it may have been associated in a reference composition or source(e.g., a natural source). In some embodiments, a composition of theinvention contains a compound described herein and less than about 25%,20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%,by weight, of other distinct chemical compounds and/or other materials.In case of doubt, a composition containing a single stereoisomer of acompound differs from a composition containing a racemic mixture of thatcompound; a particular salt of a compound differs from other salt formsof the compound; compounds having one conformational isomer ((Z) or (E))of a double bond differ from compounds having the other conformationalisomer ((E) or (Z)) of the double bond; and compounds in which one ormore atoms are of a different isotope than is present in compounds of areference preparation differ from that reference preparation.

Any compound described herein can be prepared using methods describedherein and/or known in the art. Techniques useful in synthesizing thesecompounds are accessible to one of ordinary skill in the art, and thediscussion below illustrates certain of the diverse methods availablefor use in assembling them. The discussion is not intended to limit thescope of useful reactions or reaction sequences.

The present compounds are generally prepared according to the Schemesset forth below. Schemes 1-3 are general schemes for producing compoundswhere R⁴ and R⁵ are each hydrogen, L² is a bond and R² is4-hydroxycyclohexyl. Scheme 4 is a more general scheme for synthesizingcompounds described herein. The starting material in Scheme 4,7-bromo-4-chloro-2-(methylthio)pyrrolo[2, 1-f][1,2,4]triazine, iscommercially available. L^(1′) represents either a precursor to L¹having a leaving group when L¹ is other than a bond; or a leaving groupwhen L¹ is a bond. X represents a halogen.

In Scheme 5, ring A represents phenyl; ring B a saturated heterocyclylring or a cycloalkyl ring; and ring C a partially saturated carbocyclyl,a partially saturated heterocyclyl, or a heteroaryl ring.

wherein R^(a) and R^(b) are amino substituents, such as alkyl,sulfonylalkyl, etc.

Each of the steps of any of Schemes 1-7 can be performed sequentiallywith, optionally, isolation of any intermediate (i.e., none, some, orall of the intermediates can be isolated). Further, one can useavailable techniques to protect or deprotect any particular group(s).One of ordinary skill in the art will appreciate that certain startingmaterials depicted in Schemes 1-7 may be readily interchanged with otherstarting materials or reagents to provide additional compounds asdescribed herein.

Compounds and/or other compositions provided herein (e.g.,pharmaceutical compositions) have a variety of uses, including inresearch and/or clinical settings (e.g., in methods of providing adiagnosis or prognosis and in prophylactic or therapeutic treatmentmethods).

In some embodiments, the compounds and other compositions describedherein are used in preventing or treating a cancer in a patient in needthereof (e.g., in a patient having tumor cells that express orover-express a TAM kinase or any combination of TAM kinases). In variousembodiments of these methods, one may carry out a step of obtaining abiological sample from the patient and/or detecting the presence ofand/or determining the amount of, or activity of, one or more TAMkinases in a provided biological sample (i.e., these steps areoptional). Similarly, and in any embodiment of these methods, one maycarry out other tests useful in diagnosing whether the patient hascancer and/or in characterizing the cancer (e.g., its type, grade,susceptibility to treatment, etc. . . . ) (i.e., diagnostic testing isanother optional step that can be carried out prior to or in the courseof treatment). The methods of treatment require administering to apatient in need thereof a therapeutically effective amount of a compounddescribed herein (e.g., a compound having the structure depicted inFormula I-Formula VII in a pharmaceutically acceptable composition toreduce a sign or symptom of the disease), and TAM kinases can beevaluated in biological samples obtained from the patient at anypoint(s) in time during the therapeutic regimen.

Each method (e.g., each therapeutic or diagnostic method) that employs acompound described herein and involves administration of the compound toa patient may also be expressed in terms of “use” and vice versa. Forexample, the invention encompasses: the use of a compound or compositiondescribed herein for the treatment of a disease described herein (e.g.,a cancer); a compound or composition for use in diagnosing and/ortreating a disease (e.g., a cancer); and the use of the compound orcomposition for the preparation a medicament for treating a diseasedescribed herein (e.g., a cancer).

The methods of the invention that concern diagnosing and/or treating adisease described herein (e.g., a cancer) may specifically exclude anyone or more of the types of diseases (e.g., any one or more of the typesof cancer) described herein. For example, the invention features methodsof treating cancer by administering a compound described herein (e.g., acompound of any one of Formulas I-VII) with the proviso that the canceris not a breast cancer; with the proviso that the cancer is not a breastcancer or a leukemia; with the proviso that the cancer is not a breastcancer, a leukemia, or an ovarian cancer; and so forth, with exclusionsselected from any of the diseases/cancer types listed herein and withthe same notion of variable exclusion from lists of elements relevant toother aspects and embodiments of the invention (e.g., chemicalsubstituents of a compound described herein or components of kits andpharmaceutical compositions).

A provided compound and/or a composition containing it can have activityagainst each of TYRO3, AXL and MERTK (e.g., inhibitory activity above aparticular level (e.g., a reference level) with respect to each ofTYRO3, AXL and MERTK). In some embodiments, a provided compound and/orcomposition shows specificity for only one or any two (but not all) ofTYRO3, AXL and MERTK. In some embodiments, a provided compound and/orcomposition shows more specificity for one TAM kinase than another TAMkinase or more specificity for a TAM kinase than a non-TAM kinase.

In some embodiments, a provided compound and/or composition isconsidered to be specific for a given kinase or set of kinases when itshows at least or about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold,15-fold, 20-fold, 50-fold, 100-fold or more activity for the specifickinase(s) than for one or more appropriate comparator kinase(s) (e.g.,for one or more TAM kinases relative to one or more non-TAM kinases, forone or more of TYRO3, AXL and MERTK relative to one or more kinasesother than TYRO3, AXL and MERTK, or for one or more of TYRO3, AXL, andMERTK relative to one another). In one specific aspect of theseembodiments, a provided compound and/or composition is considered to bespecific for a given kinase or set of kinases when it shows at least2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold,100-fold or more activity for the specific kinase(s) than for FLT3. In amore specific aspect of these embodiments, a provided compound and/orcomposition shows at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold,15-fold, 20-fold, 50-fold, 100-fold or lower IC₅₀ against the TAM kinasemember against which it is most active (e.g., has the lowest IC₅₀) thanagainst another kinase (e.g., FLT3). In a more specific embodiment, aprovided compound and/or composition shows at least 2-fold, 3-fold,4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold or lowerIC₅₀ against MERTK than against FLT3. One of ordinary skill in the artwill recognize the evaluating specificity in terms of “fold difference”is only one applicable measure. In any of the embodiments justdescribed, specificity can be expressed as a “percent difference.” Forexample, a provided compound and/or composition is considered to bespecific for a given kinase or set of kinases when it shows at least101%, 105%, 110%, 120%, 130%, 140%, 150%, 200%, 300%, 400%, 500% or moreactivity for the specific kinase(s) than for one or more appropriatecomparator kinase(s) (e.g., for one or more TAM kinases relative to oneor more non-TAM kinases, for one or more of TYRO3, AXL and MERTKrelative to one or more kinases other than TYRO3, AXL and MERTK, or forone or more of TYRO3, AXL, and MERTK relative to one another).

The methods of the invention include methods of inhibiting a TAM kinaseby exposing the kinase to a compound for a time and under conditionssufficient to allow the compound to inhibit the kinase. The kinasetargeted can be one or more of TYRO3, AXL and MERTK. In someembodiments, the kinase is TYRO3. In some embodiments, the kinase isAXL. In some embodiments, the kinase is MERTK. These methods can becarried out in vivo or in vitro, and analysis of TAM kinase activity canbe assessed using techniques described herein and/or well known in theart (e.g., an assay of the kinase's ability to phosphorylate itssubstrate).

In some embodiments, compounds of the present disclosure areadministered (e.g., by a route described herein) in a therapeuticallyeffective amount to treat and/or delay the onset of (e.g., prevent) adisease responsive to inhibition of one or more TAM kinases (e.g.,TYRO3, AXL and/or MERTK). Thus, a compound described herein is useful(e.g., as a therapeutic) in the treatment of cancer; is useful inpreventing cancer; and/or is useful in delaying the onset of cancer orinhibiting its metastasis and, as noted above, each therapeutic orprophylactic application may also be expressed in terms of “use” of acompound described herein. The cancer a patient has been diagnosed ashaving and/or the cancer cells contacted with a compound or compositiondescribed herein can be of the following type: a blood cancer, a bonecancer, a breast cancer (e.g., TNBC), an endocrine cancer (e.g., cancerof the thyroid, parathyroid, or adrenal gland), a gastrointestinalcancer (e.g., a gastric cancer or colorectal cancer), a genitourinarycancer (e.g., a cancer of the bladder, kidney, prostate, cervix, oruterus (e.g., an endometrial cancer)), a head and neck cancer (e.g.,cancer of the larynx), a liver cancer, a lung cancer (e.g., a non-smallcell lung cancer (NSCLC)), a melanoma (e.g., a skin cancer or acutaneous or intraocular melanoma), a nervous system or brain cancer(e.g., glioblastoma), an oral cancer (e.g., a cancer of the mouth orthroat), an ovarian cancer, a pancreatic cancer (e.g., pancreatic ductaladenocarcinoma), a plasma cell neoplasm or myeloma (typically referredto as a plasmacytoma when plasma cells form a single tumor in bone orsoft tissue or multiple myeloma when multiple tumors are formed), orrhabdomyosarcoma. The blood cancer, which may also be referred to as ahematopoietic or hematological cancer or malignancy, can be a leukemiasuch as acute lymphocytic leukemia (ALL; e.g., B cell ALL or T cellALL), acute myelocytic leukemia (AML; e.g., B cell AML or T cell AML),chronic myelocytic leukemia (CML; e.g., B cell CML or T cell CIVIL), orchronic lymphocytic leukemia (CLL; e.g., B cell CLL (e.g., hairy cellleukemia) or T cell CLL). The blood cancer can also be a lymphoma suchas Hodgkin lymphoma (HL; e.g., B cell HL or T cell HL), non-Hodgkinlymphoma (NHL; e.g., B cell NHL or T cell NHL), follicular lymphoma,chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),mantle cell lymphoma (MCL), a marginal zone B cell lymphoma (e.g.,splenic marginal zone B cell lymphoma), primary mediastinal B celllymphoma (e.g., splenic marginal zone B cell lymphoma), primarymediastinal B cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenstrom's macroglobulinemia), immunoblastic largecell lymphoma, precursor B lymphoblastic lymphoma, or primary centralnervous system (CNS) lymphoma. The B cell NHL can be diffuse large celllymphoma (DLCL; e.g., diffuse large B cell lymphoma), and the T cell NHLcan be precursor T lymphoblastic lymphoma or a peripheral T celllymphoma (PTCL). In turn, the PTCL can be a cutaneous T cell lymphoma(CTCL) such as mycosis fungoides or Sezary syndrome, angioimmunoblasticT cell lymphoma, extranodal natural killer T cell lymphoma, enteropathytype T cell lymphoma, subcutaneous anniculitis-like T cell lymphoma, oranaplastic large cell lymphoma. While the invention is not limited totreating or preventing blood cancers having any particular cause orpresentation, stem cells within the bone marrow may proliferate, therebybecoming a dominant cell type within the bone marrow and a target for acompound described herein. Leukemic cells can accumulate in the bloodand infiltrate organs such as the lymph nodes, spleen, liver, andkidney. In some embodiments, a compound of the present disclosure isuseful in the treatment or prevention of a leukemia or lymphoma. Inother embodiments, the cancer is a gastric cancer, prostate cancer,breast cancer (e.g., TNBC), pituitary adenoma, lung cancer (e.g.,NSCLC), a melanoma, glioblastoma, ovarian cancer or rhabdomyosarcoma. Insome embodiments, the cancer is a hematologic disorder, such asmyelodysplastic syndrome (MDS) or myeloproliferative disease (MPS), inwhich precursor cells in the bone marrow (e.g., stem cells) do notmature properly. Some types of MDS may develop into AML. Patients whohave been diagnosed with MDS or MPS that then transforms to AML may bereferred to as having AML or AML with myelodysplasia-related changes. Aprovided compound and/or composition containing it (e.g., apharmaceutical composition) can also be administered to cells or to apatient who has a benign lesion such as a papilloma or adenoma (e.g., apituitary adenoma). In some embodiments, the benign lesion is tuberoussclerosis. Although hematologic disorders and benign lesions generallyhave less serious consequences for a patient than cancer, we may referto these conditions as a “disease” and any are amenable to treatment andpreventative care as described herein.

The present invention provides pharmaceutical compositions comprising acompound as described herein (e.g., a compound of formula I, a sub-genusthereof, or a species thereof), or a pharmaceutically acceptable saltthereof, optionally in combination with a pharmaceutically acceptablecarrier. The compound can be any compound depicted in FIG. 1 and asnoted herein, reference to any given compound encompasses stereoisomers,tautomers, and isotopic forms.

The invention also encompasses combination therapies. Thus, any givencompound described herein can be administered to a subject alone (i.e.,as the sole active agent (e.g., TAM kinas inhibitor)) or in combination(i.e., a first compound described herein can be co-administered with asecond compound described herein or other therapeutic agent). Acombination therapy or co-administration of two or more activepharmaceutical agents includes simultaneous or sequential administrationby the same or different routes of administration.

When a provided compound is used in combination with a secondtherapeutic agent active against the same disease state, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by one of ordinary skillin the art. It will be appreciated that the amount of a providedcompound required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. It will be appreciated that, in some embodiments, providedcompounds are utilized in combination with (e.g., administered tosubjects receiving) therapy (e.g., standard of care therapy) for thetreatment of cancer, including but not limited to any of the specifictypes described herein. In some embodiments, the cancer is associatedwith elevated levels of myeloid infiltration compared to a referencecell or cancer (e.g., a normal cell or healthy (non-cancerous) tissue).

Alternatively, or additionally, in some embodiments, provided compoundsare utilized in combination with (e.g., administered to subjectsreceiving) immunotherapy. In some embodiments, such immunotherapycomprises or consists of checkpoint inhibitor therapy, vaccine therapy(e.g., cancer vaccine therapy), and/or cell therapy (e.g., CAR-T therapyand/or CAR-NK therapy). In some embodiments, provided combinations areadministered to subjects who have or will receive antibody therapy, celltherapy (e.g., CAR-T therapy and/or CAR-NK therapy), chemotherapy,hormone therapy (e.g., therapy that reduces the level of a hormoneand/or hormone receptor and/or inhibits hormone-receptor interaction orone or more downstream effects thereof), radiation therapy, and/orsurgical therapy. A provided compound and/or composition containing it(e.g., a pharmaceutical composition) can be administered to cancer cellsor a cancer patient, including to cells or a patient having any of thetypes of cancer described above, and such administration can occur inthe event the patient is being (or will be) treated with a checkpointinhibitor and/or in the event the cancer is resistant to a checkpointinhibitor (i.e., a method or use described herein may be applied to apatient who has received, is receiving, or is scheduled to receive acheckpoint inhibitor). Checkpoint inhibitors include, but are notlimited to, PD-1 inhibitors (e.g., avelumab, nivolumab, andpembrolizumab), PD-L1 inhibitors (e.g., atezolizuma and durvalumab), andCTLA4 inhibitors (e.g., ipilumumab). In some embodiments, a compounddescribed herein or a pharmaceutically acceptable salt thereof can beused to treat cancers where checkpoint inhibitors have shown limitedefficacy and/or there is high myeloid infiltration, such as pancreaticductal adenocarcinoma, ovarian cancer, TNBC, glioblastoma, andcolorectal cancer.

Compounds of the present disclosure can be prepared and administered ina wide variety of oral and parenteral dosage forms. Thus, the compoundsof the present disclosure can be formulated for administration byinjection (e.g. intravenously, intramuscularly, intracutaneously,subcutaneously, or intraperitoneally). The compounds can also beformulated for administration by inhalation (e.g., intranasally) or byinsufflation. In other embodiments, the compounds described herein canbe formulated for topical or transdermal administration (i.e., they canbe in a dosage form suitable for administration by the various routesjust described).

For preparing pharmaceutical compositions including a compound describedherein, pharmaceutically acceptable carriers can be added in eithersolid or liquid form or a combination thereof. Solid dosage formpreparations within the scope of the present invention include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be a substance that may also act as adiluent, flavoring agent, binder, preservative, tablet disintegratingagent, or an encapsulating material. In powders, the carrier is a finelydivided solid in a mixture with the finely divided active component(e.g., a compound described herein, e.g., a compound conforming to thestructure of Formula II). In tablets, the active component is mixed withthe carrier having the necessary binding properties in suitableproportions and compacted in the shape and size desired. Pharmaceuticalcompositions, including those formulated as powders and tablets, cancontain from about 5% to about 70% of the active compound. Suitablecarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, a low melting wax, cocoa butter, and thelike. Tablets, powders, capsules, pills, cachets, and lozenges can beused as solid dosage forms suitable for oral administration. Forpreparing suppositories, a low melting wax, such as a mixture of fattyacid glycerides or cocoa butter, is melted and the active component isdispersed therein.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution. When parenteral application is needed ordesired, particularly suitable admixtures for the compounds of theinvention are injectable, sterile solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants, includingsuppositories. In some embodiments, suitable carriers for parenteraladministration will be selected for human administration.

In particular, carriers for parenteral administration include aqueoussolutions of dextrose, saline, pure water, ethanol, glycerol, glycerolformal, polyethylene glycol, propylene glycol, peanut oil, sesame oil,polyoxyethylene-block polymers, pyrrolidine, N-methyl pyrrolidione, andthe like. Ampoules are convenient unit dosage forms. The compounds ofthe present disclosure can also be incorporated into liposomes oradministered via transdermal pumps or patches. Pharmaceutical admixturessuitable for use in the present disclosure include those described, forexample, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton,Pa.) and WO 96/05309, the teachings of both of which are herebyincorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical compositions are preferably in unit dosage form. Theunit dosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Unit dosage forms can also becapsules, tablets, cachets, lozenges, or the appropriate number of anyof these in packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition(e.g., polysorbate 20, 60, and 80; Pluronic® F-68, F-84, and P-103;cyclodextrin; and polyoxyl 35 castor oil). Such co-solvents aretypically employed at a level between about 0.01% and about 2% byweight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

Compositions of the present invention may additionally includecomponents to provide sustained release and/or comfort (e.g., highmolecular weight, anionic mucomimetic polymers, gelling polysaccharides,and finely-divided drug carrier substrates). These components arediscussed in detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162;and 4,861,760. The entire contents of these patents are incorporatedherein by reference in their entirety for all purposes.

Pharmaceutical compositions provided by the present disclosure includecompositions wherein the active ingredient is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. For example, when administered in methods to a subject withcancer, such compositions will contain an amount of active ingredienteffective to achieve the desired result.

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending on a variety of factors, including routeof administration; the size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated; any concurrent treatment; and complications fromany disease or treatment regimen. Other therapeutic regimens or agentscan be used in conjunction with the methods and compounds of the presentdisclosure.

For any compound or pharmaceutical composition described herein, thetherapeutically effective amount can be initially determined from, orinformed by data generated in, cell culture assays and/or animal modelsof disease. For example, a dose for humans can be formulated to achievea concentration that has been found to be effective in animals. Thedosage in humans can be adjusted by, for example, monitoring kinaseinhibition, the signs an symptoms of the disease being treated, and sideeffects and subsequently adjusting the dosage upwards or downwards.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient shouldbe sufficient to effect a beneficial therapeutic response in the patientover time. The size of the dose also will also be determined by theexistence, nature, and extent of any adverse side effects. Generally,treatment is initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under a desired circumstanceis reached. In some embodiments, the concentration of compound is about0.001% to 10% w/v (e.g., about 0.1% to about 5% w/v). In someembodiments, the concentration range is 0.1% to 5% w/v. Concentrations,dosage amounts, and intervals can be adjusted in each individual patientto provide levels of the administered compound effective for theparticular disease being treated. This will provide a therapeuticregimen commensurate with the severity of the patient's disease.

EXAMPLES

The following analytical instruments were used in the synthesis andanalysis of compounds of the invention. For liquid chromatography massspectrometry (LCMS or LC-MS): Shimadzu UFLC MS: LCMS-2020; AgilentTechnologies 1200 series MS: Agilent Technologies 6110; AgilentTechnologies 1200 series MS: LC/MSD VL; Waters Alliance HPLC system. MS:Waters Micromass ZQ; and Waters 996 PDA detector. For nuclear magneticresonance (NMR): BRUKER AVANCE III/400 MHz, Varian 400 MHz or BRUKERAVANCE II/500 MHz; for preparatory high performance liquidchromatography (prep-HPLC): Gilson GX-281 systems, instruments GX-A,GX-B, GX-C, GX-D, GX-E, GX-F, GX-G and GX-H; Waters 2767 Sample Manager,MS. Waters Micromass ZQ, Waters 2545 binary gradient module; and Waters2996 PDA detector.

Example 1: Synthesis of Intermediates A.7-bromo-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine

Step 1: methyl 1-amino-1H-pyrrole-2-carboxylate

To a solution of methyl 1H-pyrrole-2-carboxylate (100 g, 799 mmol) indimethylformamide (DMF; 1.2 L) was added NaH (51.1 g, 1.28 mol, 60%purity) at 0° C. The mixture was stirred at 0° C. for 1 hour, thenO-(2,4-dinitrophenyl)hydroxylamine (238.71 g, 1.20 mol) in DMF (300 mL)was added dropwise. The mixture was stirred at 0° C. for 3 hours. Thereaction mixture of two batches was combined and poured into aqueous(aq.) sat. sodium thiosulfate solution (10 L). The resulting mixture wasextracted with EtOAc (4 L×3). The combined organic layers were washedwith brine (2 L×3), dried over Na₂SO₄, and then filtered. The filtratewas concentrated, then purified by silica gel chromatography to affordmethyl 1-amino-1H-pyrrole-2-carboxylate (190 g, crude) as a yellow oil.

Step 2: methyl 1-(3-benzoylthioureido)-1H-pyrrole-2-carboxylate

To a solution of methyl 1-amino-1H-pyrrole-2-carboxylate (95.0 g, 647mmol) in THF (tetrahydrofuran; 2.0 L) was added a solution of benzoylisothiocyanate (137 g, 842 mmol) in THF (500 mL) at 25° C. The mixturewas stirred at 25° C. for 2 hours. Two batches were combined andconcentrated in vacuo. The residue was triturated with MTBE (methyltert-butyl ether; 1.0 L) then filtered to afford the title compound (352g, 696 mmol, 54% yield, 60% purity).

Step 3: 2-thioxo-2,3-dihydropyrrolo[2,1-f][1,2,4]triazin-4(1H)-one

A solution of methyl 1-(3-benzoylthioureido)-1H-pyrrole-2-carboxylate(140 g, 461 mmol) in aq. NaOH solution (2.0 M, 923 mL) was stirred at85° C. for 2 hours. Two batches of the reaction mixture were combinedand cooled to 0° C., to which acetic acid (300 mL) was added at 0° C.,and the resulting mixture was stirred for another 30 minutes.Precipitate was collected by filtration to afford a white solid, whichwas triturated in MTBE (2.0 L) and stirred for 20 minutes. The mixturewas filtered and washed with MTBE (500 mL). The filtered cake was driedto afford 2-thioxo-2,3-dihydropyrrolo[2,1-f][1,2,4]triazin-4(1H)-one(140 g, 754 mmol, 82% yield, 90% purity).

Step 4: 2-(methylthio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

To a solution of2-thioxo-2,3-dihydropyrrolo[2,1-f][1,2,4]triazin-4(1H)-one (57.0 g, 341mmol) in THF (1.7 L) was added MeI (69.6 g, 491 mmol) at 25° C. Themixture was stirred at 45° C. for 1 hour. Three batches were combinedand the solvent was removed in vacuo to afford an off-white solid, whichwas then treated with water (2.0 L) and aq. sat. NaHCO₃(2.0 L). Theresulting mixture was stirred for 30 minutes, then filtered to affordthe title compound (126 g, crude).

Step 5: 4-chloro-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine

To a solution of 2-(methylthio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(60.0 g, 331 mmol) in dioxane (630 mL) was added POCl₃ (phosphorylchloride; 697 g, 4.54 mol, 422 mL) at 25° C. The mixture was heated at100° C. for 4 hours. The two batches were combined, cooled to 25° C.,then poured into water (3.0 L). The pH of the mixture was adjusted to 7by adding NH_(3′)H₂O. The mixture was extracted with EtOAc (1.5 L×3).The organic layers were combined, washed with brine (2.0 L), dried overNa₂SO₄, filtered and concentrated in vacuo to give4-chloro-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (110 g, 375 mmol,57% yield, 68% purity) as a dark brown solid.

Step 6: 7-bromo-4-chloro-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine

To a solution of 4-chloro-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine(51.0 g, 255 mmol) in McOH (1.0 L) and THF (1.5 L) was added NBS(N-bromosuccinimide 45.5 g, 255 mmol) at 0° C. The resulting mixture wasstirred at 0° C. for 2 hours. Two batches were combined and the solventwas evaporated under vacuum to afford a yellow solid. The solid wasdissolved in dichloromethane (DCM; 1.0 L) and washed with water (1.0 L)then brine (0.5 L), sequentially. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give7-bromo-4-chloro-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (126.00 g,crude).

Step 7: 7-bromo-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine

A solution of7-bromo-4-chloro-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (40.0 g,144 mmol) in isopropanol (400 mL) was heated to 55° C., then treatedwith NaBH₄ (sodium tetrahydroborate; 11.40 g, 301.33 mmol). The mixturewas stirred at 55° C. for 2 hours before three batches were combined.The precipitate was filtered and washed with DCM (500 mL). The filtratewas concentrated in vacuo then re-dissolved in DCM (3.0 L).Dichlorodicyanoquinone (108 g) was then added to the solution over 15minutes. The reaction mixture was stirred at 25° C. for 30 minutes.Precipitate was filtered through Celite® and washed with DCM (500 mL).Filtrate was concentrated and purified by column chromatography to givea yellow solid (60 g), which was further purified by another columnchromatography to afford7-bromo-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (47.7 g, 93% purity)as a yellow solid.

B. (S)-5-bromo-N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

Step 1:2-(methylthio)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazine

A mixture of 7-bromo-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (2.5 g,10 mmol),2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.4 g, 12.8 mmol), Pd(dppf)Cl₂([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); 375 mg,0.512 mmol), Na₂CO₃ (4.3 g, 41 mmol) in DME (37.5 mL) and H2O (15 mL)was degassed and purged with N₂ 3 times, and then the mixture wasstirred at 90° C. for 2 hours under N₂. Upon completion, the reactionmixture was diluted with EtOAc (40 mL) and extracted with water (50 mL).The aqueous layer was separated and extracted with EtOAc (50 mL×3). Allorganic layers were combined, washed with brine (40 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography to give the title compound (2.3 g,72% yield, 98% purity) as a yellow solid.

Step 2:2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazine

To a solution of2-(methylthio)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazin(2.3 g, 7.6 mmol) in DMF (40 mL) was added m-CPBA (3.1 g, 15 mmol, 80%purity), the mixture was then stirred at 65° C. for 12 hours. Uponcompletion, the reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (EtOAc; 30 mL×4). The organic layers werecombined, washed with brine (30 mL×2), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound(1.95 g, crude) as a yellow solid.

Step 3:(S)—N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methylsulfonyl-pyrrolo[2,1-f][1,2,4]triazine(0.95 g, 2.8 mmol), (2S)-heptan-2-amine (1.14 g, 9.1 mmol),N,N-diisopropyl ethylamine (DIPEA; 1.7 mL, 9.9 mmol) and NMP(N-methyl-2-pyrrolidone; 10 mL) were added into a microwave tube, whichwas sealed and heated at 180° C. for 1 hour under microwave irradiation.DIPEA (0.247 mL, 1.4 mmol) and (2S)-heptan-2-amine (163 mg, 1.4 mmol)were then added, and the resulting mixture was heated at 180° C. foranother 1 hour under microwave irradiation. Upon completion, thereaction mixture was diluted with EtOAc (20 mL) and extracted with water(20 mL). The aqueous layer was separated, extracted with EtOAc (20mL×3). All organic layers were combined, washed with brine (20 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography to give the tittlecompound (480 mg, 46% yield, 100% purity) as a light yellow solid.

Step 4a:(S)—N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-amine

To a solution of7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(480 mg, 1.3 mmol) in McOH (60 mL) was added Pd—C(palladium on carbon;10% purity, 70 mg) under N₂. The suspension was degassed and purged withH2 several times, then stirred under H2 (40 psi) at 25° C. for 12 hours.Upon completion, the reaction mixture was filtered and concentrated invacuo to afford the title compound (430 mg, crude) as a light yellowoil.

Step 4b:(S)—N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

To a solution of(S)—N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-amine(430 mg, 1.2 mmol) in DCM (10 mL) was added MnO₂ (399 mg, 4.6 mmol). Theresulting mixture was stirred at 25° C. for 1 hour. Upon completion, thereaction mixture was filtered and concentrated in vacuo. The residue waspurified by prep-TLC (thin layer chromatography) to give the titlecompound (250 mg, 58% yield, 99% purity) as a light yellow solid.

Step 5:(S)-5-bromo-N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

To a solution of7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(250 mg, 0.671 mmol) in DCM (10 mL) was added NBS (120 mg, 0.671 mmol)at 0° C. The mixture was stirred at 25° C. for 30 minutes. Uponcompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was purified by column chromatography to give the titlecompound (300 mg, 99% yield) as a light yellow oil.

C. 5-bromo-N-butyl-7-(1,4-dioxaspiro[4.5]decan-8yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

This synthesis was carried out in a manner similar to the synthesisdescribed in Example 1, part B, substituting (S)-pentan-2-amine forn-butylamine at Step 3.

D. cis andtrans-4-(5-bromo-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol

Step 1: 7-bromo-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazine

A mixture of 7-bromo-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (25.0g, 102 mmol), and sodium tungstate dihydrate (2.08 g, 6.32 mmol) in McOH(183 mL) was treated with hydrogen peroxide solution (41.6 mL, 408mmol). The suspension was heated at 65° C. and, within 10 minutes,became homogeneous. After heating for 2 hours, a precipitate formed. Thehot mixture was treated with H₂O (25 mL) and allowed to cool slowly toRT (heating switched off, but bath maintained). The product was filteredand washed with H₂O, followed by heptane and dried under suctionovernight. A bright yellow solid (25.1 g, 89%) was obtained.

Step 2:2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazine

A mixture of 7-bromo-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazine(270 mg, 978 μmol), 1,4-Dioxaspiro[4.5]dec-7-en-8-boronic acid pinacolester (390 mg, 1.44 mmol) and sodium hydrogenocarbonate (128 μL, 3.29mmol) was suspended in 1,4-Dioxane (9.7 mL) and H2O (3 mL), and themixture was degassed by bubbling N₂ through the mixture for 5 min. Themixture was treated with[1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(11) (48.8 mg,59.7 μmol) and then heated at 90° C. for 30 mien. The reaction mixturewas cooled to RT, poured into H₂O and extracted with EtOAc (×3). Thecombined organic layers were washed (H₂O, brine), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by columnchromatography. (Combiflash, 24 g column 0 to 100% EtOAc in hexane.). Weobtained 223 mg of product.

Step 3:2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine

A suspension of2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazine(190 mg, 567 μmol) and palladium on carbon 10% loading (1.83 g, 1.72mmol) in THF (7.00 mL) and McOH (10.0 mL) was evacuated and backfilledwith N₂ five times. The mixture was then evacuated and backfilled withhydrogen five times and allowed to stir at RT with a balloon of H₂.After 4.5 hours, the mixture was evacuated and backfilled with N2 (×3)then filtered over Celite®. The reaction was concentrated in vacuo andthe residue concentrated from THF The residue was dissolved in THF (7mL) and combined with the crude reaction mixture from a 24 mg run. Itwas treated with activated manganese (IV) oxide (240 mg, 2.83 mmol) andheated at 50° C. for 30 min. After one hour, a second portion of 200 mgof MnO₂ was added. This was repeated twice more (four total additions),and the reaction was cooled to RT and filtered through Celite®, Thecrude material (194 mg) was used “as is” in the next step.

Step 4:5-bromo-2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine

A solution of 2 (methylsulfonyl)-7-(1,4-dioxaspiro[4.5]decan8-yl)pyrrolo[2,1-f][1,2,4]triazine (194 mg, 575 μcool) in CH₂Cl₂ (3.00mL) was cooled in an ice bath and treated with NBS (105 mg, 592 μmol)dissolved in DMF (1 mL). The reaction mixture was concentrated to removeDCM and partitioned between H2O and EtOAc. The layers were separated andthen the aqueous phase was extracted with EtOAc (×3). The combinedorganic layers were washed (H₂O×3, brine), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by column chromatography(CombiFlash®, 24 g column, Solvent A=50% DCM in hexanes; Solvent B=50%DCM in hexanes containing 10% iPrOH.). We obtained an orange colored gum(193 mg, 80%).

Step 5: (cis)- and(trans)-4-(5-bromo-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol

A solution of5-bromo-2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine(26.0 g, 62.5 mmol) in MeCN (400 mL) and acetone (125 mL) was cooled to0° C. and treated with hydrochloric acid (65 mL, 390 mmol) and allowedto stir for 2 h. The volatile solvents were removed, and the reactionwas dissolved in acetone (500 mL) and treated with further HCl (6M, 25mL). After stirring for a further 2 h, the reaction mixture was pouredcarefully into a stirred solution of saturated. NaHCO₃ and the mixtureallowed to stir for 20 min. The solution was extracted with EtOAc (×3),and the organic layers were washed (brine), dried (Na₂SO₄) andconcentrated in vacuo. Attempted recrystallization of the crude materialfrom hex:EtOAc was unsuccessful. Filtering the hot suspension gave 5.88g of pure ketone. The remaining material was dissolved in 75 mL acetoneand 75 MI, MeCN and treated with 50 mL of HCl 6M at 0° C. After 5 min,the ice bath was removed and the mixture was allowed to stir at RT for30 ruin. The reaction was worked up as above, and we obtained 17.92 g.The crude material was used “as is” in the next experiment.

A solution of the ketone obtained above (12.1 g, 32.6 mmol) in McOH (250mL) was cooled to 0° C., treated with sodium borohydride (5.34 g, 136mmol), and allowed to stir for 30 min. The mixture was quenched withsaturated NH₄Cl and then H2O and finally acidified to pH 2-3 with 6MHCL. The mixture was diluted with EtOAc, the layers separated, and theaq phase extracted with EtOAc (×3). The combined organic layers werewashed (H₂O, brine), dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by column chromatography (CombiFlash®, 330 gcolumn, solvent A=50% DCM in hexanes, solvent B=20% IPA in 50%DCM:hexanes) we obtained a pale yellow solid (7.3 g) as the majorproduct (trans) and a pale yellow solid (that elutes before the major)900 mg (cis).

E.(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol

A mixture of (trans) 4-(5-bromo-2-(methylsulfonylpyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol (3.73 g, 10.1 mmol),(S)-1-methoxy-2-propylamine (5.4 mL, 505 mmol) and DIPEA (4.4 mL, 25.3mmol) in NMP (9.5 mL) was sealed and heated for 4 hours at 135° C. Themixture was cooled to RT, diluted with EtOAc (100 mL), and washed withsaturated NaHCO₃ (3×), water (3×) and brine (3×). The organic phase wasdried with MgSO₄, filtered, and then concentrated under reducedpressure. We obtained a pale orange foam (3.77 g. 97%), which was used“as is” in subsequent reactions.

The following intermediates were prepared analogously to the previousintermediates, using the indicated amine:

Intermediate Name Amine Structure F (trans)-4-(5-bromo-2-(((S)-4,4,4-trifluorobutan-2- yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexan-1-ol

G (trans)-4-(5-bromo-2-(((S)-1- (difluoromethoxy)propan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

H (trans)-4-(5-bromo-2-(((S)-4- fluorobutan-2- yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexan-1-ol

I (trans)-4-(5-bromo-2-(((S)-1- cyclopropylpropan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

J (cis)-4-(5-bromo-2-(((S)-1- methoxypropan-2- yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexan-1-ol

K (trans)-4-(5-bromo-2-(((S)- 1,1,1-trifluoropropan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

L (trans)-4-(5-bromo-2-((1,1- difluoropropan-2- yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexan-1-ol

M (trans)-4-(5-bromo-2-((1- (methoxymethyl)cyclopropyl)-amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

N (trans)-4-(5-bromo-2-(((S)-4- (difluoromethoxy)butan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

O (trans)-4-(5-bromo-2-((1- ethylcyclobutyl)amino)pyrrolo-[2,1-f][1,2,4]triazin-7- yl)cyclohexan-1-ol

P (trans)-4-(5-bromo-2-(((S)-1- ethoxypropan-2- yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexan-1-ol

Q (S)-3-((5-bromo-7-((trans)-4- hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)butanenitrile

R (trans)-4-(5-bromo-2-(((S)-4- methoxybutan-2- yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexan-1-ol

S (trans)-4-(5-bromo-2-(((S)-1- isopropoxypropan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

T (trans)-4-(5-bromo-2-((1- (tetrahydrofuran-2-yl)ethyl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

U (trans)-4-(5-bromo-2-(((R)- 1,1,1-trifluoropropan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexanol

V (trans)-4-(5-bromo-2-(((S)-1- phenylethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexanol

W (trans)-4-(5-bromo-2-(((R)-1- phenylethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7- yl)cyclohexanol

BF (trans)-4-(5-bromo-2-(((S)-4,4- difluorobutan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexanol

BG (trans)-4-(5-bromo-2-(((S)-1- trideuteromethoxypropan-2-yl)amino)pyrrolo[2,1- f][1,2,4]triazin-7- yl)cyclohexan-1-ol

X. 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazol-1yl)methyl)cyclopropane carbonitrile

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg,1.01 mmol) and triphenylphosphine (397 mg, 1.52 mmol) were added in a 10mL round-bottomed flask. THF (2.00 mL) was added followed by the1-(hydroxymethyl)cyclopropanecarbonitrile (107 μL, 1.26 mmol) and thediisopropyl azodicarboxylate (304 μL, 1.52 mmol). The solution wasstirred for 48 hours. Upon completion, the solvent was removed in vacuoto give the title compound (1050 mg, crude) as a pale yellow clear oil,which was used “as is” in subsequent steps. 4-((4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridazine(Intermediate Y) was prepared analogously using4-hydroxymethylpyridazine in place of1-(hydroxymethyl)cyclopropanecarbonitrile.

Z.methyl-2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazol-1-yl)propanoate

A mixture of pyrazole-4-boronic acid pinacol ester (1.00 g, 5.15 mmol)and cesium carbonate (3.38 g, 10.3 mmol) in DMF (16.0 mL) was treatedwith methyl alpha-bromoisobutyrate (1.01 mL, 7.73 mmol) and the mixturewas allowed to stir at RT for 2 days. The crude mixture was thenconcentrated to dryness, diluted with EtOAc and water and slowlyacidified with 1N HCl (pH=5-6). The organic phase was washed with HCl1N, then the aqueous phase was extracted three times with EtOAc. Thecombined organic phases were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The crude mixture was purified on a40 g silica column (dry pack) eluting with (A) hexanes and (B) MTBE(gradient started at 5% and the product started to be collected at 40%MTBE). After evaporation of the volatiles, the title product wasobtained as a white solid (988 mg, 61%).

AA.5-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)methyl)-1,2,4-oxadiazole

Pyrazole-4-boronic acid pinacol ester (106 mg, 0.535 mmol),3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (145 mg, 1.07 mmol) andpotassium carbonate (142 mg, 1.03 mmol) were added in vial undernitrogen. Anhydrous DMF (1.5 mL) was then added and the reaction mixturewas heated to 50° C. overnight. The remaining salts were filtered offand after evaporation of the volatiles under reduced pressure, the titleproduct was used onto the next step (69 mg, 47%).

The following intermediates were prepared analogously to the indicatedintermediate using the indicated alkylating agent.

Analagous Intermediate Name Intermediate Alkylating agent Structure AB1-(2- (methylsulfonyl)ethyl)- 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole Z

AC 2-methyl-5-((4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)methyl)-1,3,4- oxadiazole AA

AD methyl 2-(4-iodo-1H- pyrazol-1-yl)-2- methylpropanoate Z

AE 5-((4-iodo-1H- pyrazol-1-yl)methyl)- 3-methyl-1,2,4- oxadiazole AA

AF 1-((tetrahydro-2H- pyran-4-yl)methyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole Z (ACN 90° C.)

AG.(S)-1-((tetrahydrofuran-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step 1:4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrazole

Pyrazole-4-boronic acid pinacol ester (2.00 g, 10.3 mmol) was weighedinto a round bottom flask, which was then fitted with a stirring bar andcapped with a septum. DCM (40.0 mL) was added to the flask and themixture was left to stir until dissolution occurred. p-toluenesulfonylchloride (2.38 g, 12.4 mmol) was added to the mixture and the solutionwas cooled to 0° C. in an ice bath. Triethylamine (TEA; 1.89 mL, 13.4mmol) was then added to the mixture dropwise via syringe. The mixturewas allowed to stir at 0° C. for 10 minutes, then warmed to RT and leftto stir overnight. Upon completion, the mixture was quenched withaqueous sodium bicarbonate and diluted with DCM. The phases wereseparated and the aqueous phase was extracted with DCM (2×). The organicphases were combined and washed with brine, then dried over MgSO₄,filtered and concentrated under reduced pressure. The crude was obtainedas a white solid (3.42 g, 95%) and was used “as is” in the followingreaction.

Step 2:(5)-1-((tetrahydrofuran-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg,0.574 mmol), cesium carbonate (207 mg, 0.632 mmol),(S)-(tetrahydrofuran-2-yl)methanol (79.4 mg, 0.747 mmol) were all addedto a sealed tube containing 2.0 mL of MeCN. This mixture was heatedovernight at 90° C. Upon completion, this mixture was concentrated underreduced pressure and used onto the next reaction as is (160 mg, crude).

The following were prepared analogously, using the alcohol indicated:

Intermediate Name Alcohol Structure AH (R)-1- ((tetrahydrofuran-2-yl)methyl)-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole

AI (S)-tert-butyl 3-(4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)pyrrolidine-1- carboxylate

AJ (S)-tert-butyl 3-(4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)pyrrolidine-1- carboxylate

AK 2-methyl-6-((4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)methyl)pyrazine

AL 2-methyl-5-((4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)methyl)pyrazine

AM 2-((4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)- 1H-pyrazol-1-yl)methyl)pyrazine

AN 4-iodo-1-(oxetan-2- ylmethyl)-1H-pyrazole

AO 1-((3S,3aS,6aR)- hexahydrofuro[2,3- b]furan-3-yl)-4-iodo- 1H-pyrazole

AP 4-((4-iodo-1H-pyrazol- 1-yl)methyl)-1- methylpyrrolidin-2- one

AQ 3-(4-iodo-1H-pyrazol- 1-yl)-1- methylpyrrolidin-2- one

AR (3R,3aR,6S,6aR)-6-(4- iodo-1H-pyrazol-1- yl)hexahydrofuro[3,2-b]furan-3-ol

AS (S)-5-((4-bromo-1H- pyrazol-1- yl)methyl)pyrrolidin- 2-one

AT (R)-5-((4-bromo-1H- pyrazol-1- yl)methyl)pyrrolidin- 2-one

AU (S)-3-(4-bromo-1H- pyrazol-1- yl)pyrrolidin-2-one

AV (R)-3-(4-bromo-1H- pyrazol-1- yl)pyrrolidin-2-one

AW 1-((1H-pyrazol-4- yl)methyl)-4-bromo- 1H-pyrazole

AX 5-((4-bromo-1H- pyrazol-1-yl)methyl)- 1,3-dimethyl-1H- pyrazole

AY 5-((4-bromo-1H- pyrazol-1-yl)methyl)- 1-methylpyridin- 2(1H)-one

AZ 4-(4-bromo-1H- pyrazol-1- yl)tetrahydro-2H- thiopyran 1,1-dioxide

BA 4-((4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)- 1H-pyrazol-1-yl)methyl)pyrrolidin- 2-one

BB 1-(4- (methylsulfonyl)benzyl)- 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole

BH 2-((4-iodo-1H-pyrazol- 1-yl)methyl)-5-methyl- 1,3,4-thiadiazole

BC. Methyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)azetidine-1-carboxylate

Step 1:1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

tert-Butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(100 mg, 0.275 mmol) was dissolved in DCM (3.0 mL). TFA (0.425 mL, 5.50mmol) was then added and the mixture was stirred at RT for 2 hours. Uponcompletion, the mixture was concentrated and the crude product was usedinto the next reaction “as is” (65 mg).

Step 2: methyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

1-(Azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(70 mg, 0.281 mmol) was dissolved in a mixture of EtOH (5.0 mL) andwater (0.5 mL). Sodium hydrogencarbonate (47.2 mg, 0.562 mmol) andmethyl chloroformate (0.03 mL, 0.384 mmol) were then added. Theresulting mixture was stirred at RT for 3 hours. Upon completion, themixture was concentrated and the crude product was used into the nextreaction “as is.”

BD.4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-pyrazole

In a flame dried flask,1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(71 mg, 0.285 mmol) was dissolved in DCM (3.0 mL). Then,2,2,2-trifluoroethyl trifluoromethanesulfonate (88.7 mg, 0.371 mmol) andDIPEA (0.055 mL, 0.2314 mmol) were added under nitrogen and the reactionmixture was stirred at RT. Upon completion, the reaction mixture wasconcentrated under reduced pressure and the crude material was used inthe next reaction “as is.”

BE. 2-(2-(4-iodo-1H-pyrazol-1 yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole(General Method A)

Step 1: 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid

Methyl 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoate (500 mg, 1.70 mmol)was dissolved in EtOH (33.6 mL) and then 1N NaOH (34.0 mL, 34.0 mmol)was added. The resulting mixture was stirred at RT for 1 hour. Uponcompletion, the reaction was quenched with 36 mL of HCl 1N and thendiluted with brine and EtOAc. The aqueous phase was extracted 3× withEtOAc. The combined organic phases were dried with MgSO₄, filtered andconcentrated under reduce pressure to give the title product (635 mg,crude), as a white solid.

Step 2: N′-acetyl-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanehydrazide

2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid (175 mg, 625 μmol) wasdissolved in dry acetonitrile (ACN; 4.5 mL) and DIPEA (241 μL, 1.37mmol) was added, followed by acethydrazide (119 mg, 1.56 mmol) and HATU((dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]yridine-3-yloxy)methaniminiumhexafluorophosphate; 291 mg, 750 μmol). The resulting mixture wasstirred overnight at RT. Upon completion, the solvent was removed underreduced pressure and the residue was diluted with EtOAc and successivelywashed with HCl 1 N, aqueous saturated NaHCO₃ and brine. The organicphase was dried with MgSO4, filtered and then concentrated under reducedpressure. The crude residue was directly used in the next step withoutfurther purification. The title product was obtained as a white solid(250 mg).

Step 3:2-(2-(4-iodo-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole

N′-acetyl-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanehydrazide (125 mg,372 μmol) was dissolved in dry THF (5 mL) and then the burgess reagent(232 mg, 930 μmol) was added. The resulting solution was then heated at60° C. for 15 hours. Upon completion, the reaction was diluted withEtOAc and water and the organic phase was washed with HCl 1N, aqueoussaturated NaHCO₃ and brine. The organic phase was dried with MgSO₄,filtered and concentrated under reduce pressure. The resulting crudewhite solid (84.5 mg) was directly used in the next step without furtherpurification.

BI: 2-(2-(4-iodo-1H-pyrazol-1 yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole

Step 1: 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid

Methyl 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoate (500 mg, 1.70 mmol)was dissolved in EtOH (33.6 mL) and then 1N NaOH (34.0 mL, 34.0 mmol)was added. The resulting mixture was stirred at RT for 1 hour. Uponcompletion, the reaction was quenched with 36 mL of HCl 1N and thendiluted with brine and EtOAc. The aqueous phase was extracted 3× withEtOAc. The combined organic phases were dried with MgSO₄, filtered andconcentrated under reduce pressure to give the title product (635 mg,crude), as a white solid.

Step 2: N′-acetyl-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanehydrazide

2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid (175 mg, 625 μmol) wasdissolved in dry ACN (4.5 mL) and DIPEA (241 μL, 1.37 mmol) was added,followed by acethydrazide (119 mg, 1.56 mmol) and HATU (291 mg, 750μmol). The resulting mixture was stirred overnight at RT. Uponcompletion, the solvent was removed under reduced pressure and theresidue was diluted with EtOAc and successively washed with HCl 1N,aqueous saturated NaHCO₃ and brine. The organic phase was dried withMgSO₄, filtered and then concentrated under reduced pressure. The cruderesidue was directly used in the next step without further purification.The title product was obtained as a white solid (250 mg).

Step 3:2-(2-(4-iodo-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole

N′-acetyl-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanehydrazide (125 mg,372 μmol) was dissolved in dry THF (5 mL) and then the burgess reagent(232 mg, 930 μmol) was added. The resulting solution was then heated at60° C. for 15 hours. Upon completion, the reaction was diluted withEtOAc and water and the organic phase was washed with HCl 1N, aqueoussaturated NaHCO₃ and brine. The organic phase was dried with MgSO₄,filtered and concentrated under reduce pressure. The resulting crudewhite solid (84.5 mg) was directly used in the next step without furtherpurification.

BJ. (S)—N′-(2-(4-iodo-1H-pyrazol-1yl)-2-methylpropanoyl)tetrahydrofuran-2-carbohydrazide

Step 1: 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanehydrazide

To a solution of 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid (1.33mL, 3.57 mmol) N,N-Diisopropylethylamine; (1.37 mL, 7.82 mmol) in DMF(25.0 mL) was added HATU (1.62 g, 4.14 mmol). The mixture was stirredfix 10 min. Hydrazine (25 mL, 3.57 mmol) was added and the Obtainedmixture at room temperature (1L′1′) for 10 minutes. The reaction mixturewas diluted with. EtOAc and washed sat NaHCO₃ (×3), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gelchromatography using 20% McOH, 2.5% NH₄OH in DCM. LCMS: m/z 294.9(M=H)+.

Step 2:(S)—N′-(2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoyl)tetrahydrofuran-2-carbohydrazide

2-(4-iodo-1H-pyrazol-1-yl-2-methylpropanehydrazide (200 mg, 680 μmol)was dissolved in MIT (15 mL). To the solution was added DIPEA (199 μL,2.04 mmol) and the mixture was cooled to 0° C. and(s)-(+)-tetrahydro-2-furoic acid (49.5 uL, 505 μmol) was added. Thesolution was then stirred at RT overnight. The mixture was evaporatedand purified by flash using 20% MeOH in DCM/DCM (10-50%). LCMS:m/z=393.0 (M+H)+. The diacylhydrazides so obtained were cyclized usingthe conditions indicated in the Table below.

The following intermediates were prepared analogously to the indicatedintermediate using the indicated cyclization conditions:

Cyclization Intermediate General Method Stucture conditions BK BI

TFAA/Hunig's base/ DMF/ON BL BI

Burgess reagent/ THF/microwave/ 120° C./30 min BM BJ

Burgess reagent/ THF/microwave/ 120° C./30 min BN BJ

TFAA/DMF/0° C. to RT overnight BO BJ

Burgess reagent/ THF/microwave/ 80° C./60 min BP BJ (CDI/Hunig'sbase/DMF/DCM 0° C. then morpholine, microwave 120° C./30 min

Burgess reagent/ THF/microwave/ 120° C./30 min

BQ and BR: 2-(4-iodo-1H-pyrazol-1 yl)-2-methyl-1-morpholinopropan-1-one(Intermediate BQ) and2-methyl-1-morpholino-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazol-1yl)propan-1-one (Intermediate BR)

Step 1: 2-(4-iodo-1H-pyrazol-1-yl)-2-methyl-1-morpholinopropan-1-one

To a solution of 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid (461nag, 1.43 mmol), morpholine (317 μL, 3.58 mmol) andN,N-Diisopropylethylamine (550 μL, 3.14 mmol) in DMF (10 mL) was addedHATU (652 mg, 1.66 mmol). The resulting mixture was stirred at 55° C.overnight. The residue was diluted with H2O and extracted with EtOAc(×3). The combined layers were washed (H₂O×4), brine, dried (Na₂SO₄) andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with 0 to 80% EtOAc in hexanes to afford the desiredproduct (347 mg, 69%). ¹H NMR (500 MHz, CDCl₃) δ 7.57-7.54 (m, 1H), 7.52(d, J=0.5 Hz, 114), 3.48 (s. 8H), 1.78 (s. 6H). LCMS m/z 349.9 (M+H)+.

Step 2:2-methyl-1-morpholino-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-one

In a flame-dried flask was added DMSO (dimethyl sulfoxide; 2. mL) whichwas degassed with argon for 10 min (bubbling with a long needle, in asonication bath), KOAc (142 mg, 1.43 mmol), Bis(pinacolato)diboron (175mg, 676 μmol) and2-(3-iodo-1H-pyrrol-1-yl)-2-methyl-1-morpholinopropan-1-one (200 mg, 573μmol) were then added and the reaction mixture was degassed again for 10mill and then stirred at RT for 20 min. PdCl₂dppf was then added and theresulting mixture was stirred overnight at 90° C. The residue wasdiluted with H₂O and extracted with EtOAc (×3). The combined layers werewashed (sat NH₄Cl, sat NaHCO₃, brine, dried (Na₂SO₄) and concentrated.The residue was purified by column chromatography on silica gel, elutingwith 0 to 20% IPA in DCM to afford the desired product (143 mg, 72%).LCMS m/z=350.1 (M+H)⁺.

The following were prepared analogously to BQ and BR:

Intermediate Structure BS

BT

BU

BV

BW: 4-chloro-2-(oxetan-3-yl)pyridine

The indicated ligand was prepared as described in J. Org. Chem. 82:7085,2017. In a flame dried 5 mL microwave vial was successively addeddimethyl adipate (DMA; 5 mL), ligand (15.3 mg, 65.0 μmol), nickelchloride, dimethoxyethane adduct (14.7 mg, 65.0 μmol), sodium iodide(48.7 mg, 325 μmol) 2-Bromo-4-chloropyridine (286 μL, 1.30 mmol),3-bromooxetane (162 μL, 1.95 mmol) zinc (173 mg, 2.60 mmol),trifluoroacetic acid (10.0 μL, 130 μmol). The vial was capped and argonwas bubbled into the solution for 8 minutes in the sonic bath. Thereaction mixture was heated to 60° C. with stirring overnight thenfiltered through a Celite® pad subsequently washed with EtOAc. Thefiltrate was then washed with 5% aq NH₄OH. The organic layer was washedwith brine, dried over MgSO₄, and filtered, and concentrated in vacuo.The residue was purified by column chromatography (silica gel andeluting with 10 to 100% EtOAc in heptane). We obtained a pale yellow oil(41.0 mg, 19%). LCMS m/z=350.1 (M+H)⁺.

BX: 2-(4-bromopyridin-2-yl)propan-2-ol

Methyl 4-bromopicolinate (500 mg, 2.31 mmol) was dissolved in dry THF(10 mL) under argon at 0° C. and MeMgBr (1.70 mL, 5.09 mmol) was addeddropwise. After 30 min, the solution was stirred for 1 hour at RT thenstored “as is” at −17° C.; overnight. The resulting solution was dilutedwith water and extracted with EtOAc (×2). The organic phase was driedwith MgSO₄ filtered and then concentrated under reduced pressure. Theresidue was purified on a 12 g silica column eluting with 5 to 100%EtOAc in hexanes. The desired product was obtained as a colorless oil(256 mg, 51%). LCMS m/z=215.8/217.8 (M+H)H.

BY: 1-((5-bromopyridin-2yl)methyl)-4-methylpiperazine

To a solution of 5-Bromo-2-(bromomethyl)pyridine (70.0 mg, 279 μmol) inMeCN (1 mL), cesium carbonate (137 mg, 418 μmol) was added. Theresulting slurry was stirred at RT and 1-methylpiperazine (46.4 μL, 418μmol) was added. The mixture was stirred at RT for 1 hour. Theso-obtained solution of the crude product (also containing thequaternary salt) was used “as is” in the next step.

Preparation of Amines: Amine for Intermediate F:(S)-4,4,4-trifluorobutan-2-amine hydrochloride

Step 1:(S)-2-methyl-N—((S)-4,4,4-trifluorobutan-2-yl)propane-2-sulfinamide

A mixture of 4,4,4-trifluorobutan-2-one (5 g, 39.7 mmol, 1 eq),2-methylpropane-2-sulfinamide (4.8 g, 39.7 mmol, 1.0 eq) and Ti(OEt)₄(16.4 mL, 79.3 mmol, 2 eq) in THF (30 mL) was degassed and purged withN₂ 3 times, and then the mixture was heated to 75° C. for 16 hours. TLCindicated that one new spot was formed (UV=254 nm), then the mixture wascooled to RT and then cooled to −50° C., NaBH₄ (6.0 g, 158.6 mmol, 4.0eq) was added slowly to the mixture at −50° C., the mixture was stirredat this temperature for 2 hours. Upon completion, the reaction mixturewas poured into ice water of saturated Na₂CO₃ (200 mL) and diluted withDCM (200 mL). The mixture was then filtered, and the filtrate wasextracted with DCM (200 mL×3). The combined organic layers were washedwith brine (200 mL×2), dried over anhydrous Na₂SO₄, concentrated invacuum to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/EtOAc=10/1 to 5/1) to give thetittle compound (5.3 g, 58% yield,) as a yellow solid. LCMS: (ES+) m/z(M+H)⁺=232.0.

Step 2: (S)-4,4,4-trifluorobutan-2-amine hydrochloride

To a solution of2-methyl-N-(3,3,3-trifluoro-1-methyl-propyl)propane-2-sulfinamide (1 g,4.3 mmol, 1 eq) in DCM (2 mL) was added HCl/EtOAc (4 M, 2 mL, 1.85 eq).The mixture was stirred at 25° C. for 0.25 hours. Upon completion, thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was purified by re-crystallized from DCM (5 mL) toafford 4,4,4-trifluorobutan-2-amine hydrochloride (0.6 g, 84.84% yield)as a white solid, confirmed by ¹H NMR.

Amine for Intermediate G: (S)-1-(difluoromethoxy)propan-2-aminehydrochloride

Step 1: (S)-tert-butyl (1-(difluoromethoxy)propan-2-yl)carbamate

To a solution of (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (2.40 g,13.4 mmol) and potassium acetate (3.99 g, 40.3 mmol) in DCM (9.60mL)/water (9.60 mL) was added (bromodifluoromethyl)trimethylsilane (3.19mL, 20.1 mmol). The resulting mixture was stirred at RT for 7 days. Uponcompletion, DCM and water were added. The aqueous layer was extracted 3times with DCM. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure (3g, crude).

Step 2: (S)-1-(difluoromethoxy)propan-2-amine hydrochloride

To a solution of (S)-tert-butyl(1-(difluoromethoxy)propan-2-yl)carbamate (3 g, 13.3 mmol) in McOH (25mL) was added hydrochloric acid (33.5 mL, 134 mmol). The resultingmixture was stirred at RT for 3 hours. Upon completion, the volatileswere evaporated under reduced pressure. The residue was triturated withMTBE (difluoromethoxy)propan-2-amine hydrochloride (1.29 g, crude).

Amine for Intermediate H: (S)-1-fluoropropan-2-amine hydrochloride salt

Step 1: (S)-3-(4-hydroxybutan-2-yl)-4,5-diphenyloxazol-2(3H)-one

A mixture of (S)-3-Aminobutan-1-ol (4.25 mL, 42.0 mmol) and4,5-diphenyl-1,3-dioxol-2-one (10.0 g, 42.0 mmol) in DMF (125 mL) wasallowed to stir at RT overnight. The reaction was diluted with H2O andextracted with EtOAc (×5), and the combined organic layers washed(H₂O×5, brine), dried (Na₂SO₄) and concentrated in vacuo. The residuewas treated with TFA (39.0 mL, 504 mmol) and the solution was allowed tostir for 2 hours. The solution was concentrated and the residue taken upin McOH and treated with K2CO₃ (11.9 mL, 210 mmol) and the mixture wasallowed to stir for 1 hour. The mixture was concentrated and the residuewas diluted with H2O and extracted with EtOAc (×3), and the combinedorganic layers washed (H₂O×2, brine), dried (Na₂SO₄) and concentrated invacuo. The residue was purified by column chromatography (0 to 100%EtOAc in hexanes) to give a colorless solid (7.60 g, 59%).

Step 2: (S)-3-(1-fluoropropan-2-yl)-4,5-diphenyloxazol-2(3H)-one

A solution of (S)-3-(4-hydroxybutan-2-yl)-4,5-diphenyloxazol-2(3H)-one(1.00 g, 3.23 mmol) in Toluene (10 mL) was treated with2-pyridinesulfonyl fluoride (603 mg, 3.56 mmol) followed by1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (971 μL, 6.37 mmol) dropwise atRT overnight. The mixture was diluted with 8 mL DCM and stirringcontinued for a further 24 h. The DCM was removed in vacuo, and theresidue was diluted with H2O and extracted with EtOAc (×3). The combinedorganic layers were washed (H₂O, brine), dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by column chromatography (Combiflash,12 g column, 0 to 100% EtOAc in hexanes). We obtained a colorless solid(411 mg, 41%).

Step 3: (S)-1-fluoropropan-2-amine hydrochloride salt

A solution of (S)-3-(4-fluorobutan-2-yl)-4,5-diphenyloxazol-2(3H)-one(405 mg, 1.30 mmol) in McOH (10 mL) containing HCl (542 μL, 6.50 mmol)and palladium 10% wt on activated carbon (400 mg) was hydrogenated undera balloon at 50° C. overnight. The mixture was filtered through Celite®and the residue concentrated. ¹H NMR showed a mixture, and wasconsistent with the desired product and diphenylethane. The crudematerial was used “as is” in subsequent steps. Assume theoretical yield.

Amine for Intermediate N: (S)-4-(difluoromethoxy)butan-2-aminehydrochloride

Step 1: (S)-tert-butyl (4-hydroxybutan-2-yl)carbamate

To a solution of (S)-3-Aminobutan-1-ol (2.00 g, 22.4 mmol) in DCM (10.0mL) was added TEA (4.74 mL, 33.7 mmol) and di-tert-butyl dicarbonate(5.67 mL, 24.7 mmol). The resulting mixture was stirred at RT for 16hours. Upon completion, ice water was added, then the aqueous layer wasextracted twice with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give the title compound (4.12 g, crude).

Step 2: (S)-tert-butyl (4-(difluoromethoxy)butan-2-yl)carbamate

To a solution of (S)-tert-butyl (4-hydroxybutan-2-yl)carbamate (1.00 g,5.28 mmol) and potassium acetate (1.57 g, 15.9 mmol) in DCM (3.78mL)/water (3.78 mL) was added (bromodifluoromethyl)trimethylsilane (1.26mL, 7.93 mmol). The resulting mixture was stirred at RT for 4 days. Uponcompletion, DCM and water were added. The aqueous layer was extractedthree times with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound (1.26 g, crude).

Step 3: (S)-4-(difluoromethoxy)butan-2-amine hydrochloride

To a solution of (S)-tert-butyl (4-(difluoromethoxy)butan-2-yl)carbamate(630 mg, 2.63 mmol) in McOH (9.41 mL) was added hydrochloric acid (6.58mL, 26.3 mmol). The resulting mixture was stirred at RT for 4 hours.Upon completion, the volatiles were evaporated under reduced pressure.The residue was triturated with MTBE and filtered to give(S)-4-(difluoromethoxy)butan-2-amine hydrochloride (399 mg, crude).

Amine for Intermediate BF: (S)-4,4-difluorobutan-2-amine hydrochloride

Step 1: (S)-3-(2-oxo-4,5-diphenyloxazol-3(2H)-yl)butanal

To a solution of3-[(1S)-3-hydroxy-1-methyl-propyl]-4,5-diphenyl-oxazol-2-one (5 g, 16.16mmol, 1 eq) in DCM (50 mL) was added DMSO (3.79 mL, 48.5 mmol, 3 eq),TEA (6.75 mL, 48.5 mmol, 3 eq) and pyridine; sulfur trioxide (5.14 g,32.3 mmol, 2 eq) at 0° C. Then the mixture was stirred at 25° C. for 16hours. Upon completion, the mixture was concentrated in vacuo. Theresidue was diluted with water (50 mL) and extracted with EtOAc (3×30mL). The combined organic layer was washed with brine (2×20 mL), driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/EtOAc=6:1) to give thetitle compound (2.7 g, 54% yield) as a white solid.

Step 2: (S)-3-(4,4-difluorobutan-2-yl)-4,5-diphenyloxazol-2(3H)-one

To a solution of (3S)-3-(2-oxo-4,5-diphenyl-oxazol-3-yl)butanal (2.3 g,7.5 mmol, 1 eq) in dry DCM (45 mL) was added DAST (12.1 g, 74.8 mmol,9.9 mL, 10 eq) at 0° C. Then the mixture was stirred at 15° C. for 16hours. On completion, the mixture was quenched by sat. NaHCO₃(50 mL),and extracted with DCM (50 mL×2). The combined organic layer was washedwith water (30 mL) and brine (30 mL), dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by column chromatography (SiO₂,Petroleum ether/EtOAc=20/1) to give the title compound (1.9 g, 76%yield) as a yellow oil.

Step 3: (S)-4,4-difluorobutan-2-amine hydrochloride

To a solution of3-[(1S)-3,3-difluoro-1-methyl-propyl]-4,5-diphenyl-oxazol-2-one (2.2 g,6.68 mmol, 1 eq) in EtOH (80 mL) was added HCl (12 M, 2.78 mL, 5 eq) andPd/C (2.83 g, 1.34 mmol, 5% purity, 0.2 eq) under N₂. The suspension wasdegassed under vacuum and purged with H2 several times. The mixture wasstirred under H2 (15 psi) at 80° C. for 16 hours. Upon completion, themixture was filtered and the filtrated was concentrated in vacuo to givea crude product. To the residue was added 20 mL of petroleum ether/EtOAc(1:1) and 1 N HCl (30 mL). The aqueous layer was extracted withpetroleum ether/EtOAc (1:1) (20 mL×2). The combined organic was washedwith 1 N HCl (30 mL). The organic phase was discarded. The aqueous layerwas combined and lyophilized to give the title compound (950 mg, 98%yield) as a white solid.

Amine for Intermediate BG: (S)-1-(D3)-methoxypropan-2-amine (TFA salt)

To a solution of (S)-2-(Boc-amino)-1-propanol (1) (1.00 g, 5.71 mmol) inDMF (12 mL) at 0° C. was added sodium hydride (750 mg, 18.7 mmol) andthe reaction was stirred for 30 min. The mixture was a white paste butstill mixable. Iodomethane-d3 (497 μL, 7.99 mmol) was added dropwise at0° C. and then the reaction was allowed to warm up to RT and furtherstirred 4 hours. The reaction was diluted with water and extracted (2×)with EtOAc. The organic phase was washed with brine and dried overMgSO₄, filtered and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography on a 30 gcolumn eluting with 10% to 60% EtOAc in hexanes, affording a colorlessoil (638 mg, 58%). The product was diluted in DCM (5 mL) and treatedwith TFA (3 mL) was added. After stirring at RT for 3 h, toluene wasadded and concentrated under reduce pressure. This was repeated 3 times.The amine salt so obtained was used directly in the next step.

Example 2: Synthesis of Compound 102 and 103

Compounds 102 and 103 (as shown in FIG. 1) were synthesized according toGeneral Scheme 1, above. The step numbers indicated below correspond tothe steps shown in that scheme.

Step 1:(S)-4-(5-bromo-2-(heptan-2-ylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

To a solution of5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(180 mg, 0.399 mmol) in MeCN (5.0 mL) was added aq. HCl (6 M, 5.0 mL).The mixture was stirred at 25° C. for 1 hour. Upon completion, thereaction mixture was adjusted pH by NaHCO₃ to 6-7, then extracted withEtOAc (30 mL×3). The organic layers were combined, washed with water (30mL), brine (30 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the tittle compound (210 mg, crude) as alight yellow solid.

Step 2:(S)-4-(2-(heptan-2-ylamino)-5-(4-(morpholinosulfonyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

A mixture of4-[5-bromo-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanone(100 mg, 0.246 mmol),4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylmorpholine(95 mg, 0.270 mmol), Pd(PPh₃)₄ (tetrakis(triphenylphosphine)palladium(O); 28 mg, 0.025 mmol), Na₂CO₃ (78 mg, 0.737 mmol) in dioxane(6.0 mL) and H₂O (2.0 mL) was degassed and purged with N₂ for 3 times,and then stirred at 80° C. for 2 hours under N₂ atmosphere (atm). Uponcompletion, the reaction mixture was diluted with DCM (20 mL) andextracted with DCM (20 mL×3). The organic layers were combined, washedwith water (20 mL), brine (20 mL×2) sequentially, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep-TLC to give the tittle compound (62 mg, 0.112 mmol, 46% yield) as alight yellow solid.

Step 3:(1S,4r)-4-(2-((S)-heptan-2-ylamino)-5-(4-(morpholinosulfonyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanoland(1R,4s)-4-(2-((S)-heptan-2-ylamino)-5-(4-(morpholinosulfonyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

To a solution of4-[2-[[(1S)-1-methylhexyl]amino]-5-(4-morpholinosulfonylphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanone(54 mg, 0.098 mmol) in McOH (20.0 mL) was added NaBH₄ (19 mg, 0.390mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Uponcompletion, the reaction mixture was quenched by aq. sat. NH₄Cl (30 mL).The mixture was then extracted with DCM (20 mL×3). The organic layerswere combined, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-HPLC. The eluent wasconcentrated to remove organic solvent, treated with aq. HCl (0.2 M, 0.5mL) and then lyophilized to give4-[2-[[(1S)-1-methylhexyl]amino]-5-(4-morpholino-sulfonylphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanolas HCl salt (37 mg, 67% yield, 98% purity) and4-[2-[[(1S)-1-methylhexyl]amino]-5-(4-morpholinosulfonylphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanolas HCl salt (3.2 mg, 5.9% yield, 99% purity) as light yellow solids. Thestructure and purity of the title compounds were confirmed by ¹H NMR andLCMS.

Example 3: Synthesis of Compound 106

Compound 106 (as shown in FIG. 1) was synthesized according to GeneralScheme 1, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 4:(S)—N5-(4-fluorophenyl)-N2-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-2,5-diamine

A mixture of5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(80 mg, 0.177 mmol), 4-fluoroaniline (30 mg, 0.266 mmol), Cs₂CO₃ (116mg, 0.355 mmol), Brettphos-Pd-G3 (16 mg, 0.018 mmol; “Brettphos” beingdicyclohexyl(2,4,6-triisopropyl-3,6-dimethoxy-[1,1-biphenyl]-2-yl)phosphine)in dioxane (5 mL) was degassed and purged with N₂ for 3 times, and thenstirred at 60° C. for 12 hours under N₂ atm. After that, 4-fluoroaniline(30 mg, 0.266 mmol), Brettphos-Pd-G3 (16 mg, 0.018 mmol) and Cs₂CO₃ (58mg, 0.177 mmol) were added to the mixture. Then the mixture was stirredat 60° C. for 4 hours under N₂ atm. Upon completion, the reactionmixture was concentrated in vacuo. The residue was diluted with EtOAc(30 mL) and extracted with EtOAc (20 mL×3). The organic layers werecombined, washed with water (20 mL), brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC to give the title compound (110 mg, crude) as ayellow oil.

Step 6a:(S)-4-(5-((4-fluorophenyl)amino)-2-(heptan-2-ylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

To a solution of7-(1,4-dioxaspiro[4.5]decan-8-yl)-N5-(4-fluorophenyl)-N₂-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazine-2,5-diamine(100 mg, 0.208 mmol), ACN (5 mL) was added aq. HCl (6 M, 5 mL). Themixture was stirred at 25° C. for 30 minutes. Upon completion, thereaction mixture was added NaHCO₃ to adjust pH to 6-7, and thenextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the tittle compound (90 mg, crude) as ared solid.

Step 6b:(1S,4r)-4-(5-((4-fluorophenyl)amino)-2-((S)-heptan-2-ylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolhydrochloride

To a solution of4-[5-(4-fluoroanilino)-2-[[(1S)-1-methylhexyl]amino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanone(85 mg, 0.194 mmol) in McOH (5 mL) was added NaBH₄ (29 mg, 0.777 mmol).The mixture was stirred at 0° C. for 30 minutes. Upon completion, thereaction mixture was quenched by addition saturated NH₄C₁(30 mL) at 0°C., and then extracted with DCM (20 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by prep-HPLC. The eluent wasconcentrated to remove organic solvent, adjusted by aq. HCl (0.2 M, 0.5mL), and lyophilized to give the title compound (8 mg, 8.5% yield, 98%purity) as a red solid. The structure and purity of the title compoundwere confirmed by LCMS and ¹H NMR.

Example 4: Synthesis of Compound 115

Compound 115 (as shown in FIG. 1) was synthesized according to GeneralScheme 1, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 4:5-[4-(dimethylamino)-1-piperidyl]-7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine

A mixture of(S)-5-bromo-N-(heptan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(90 mg, 0.199 mmol), N,N-dimethylpiperidin-4-amine (38 mg, 0.299 mmol),t-BuONa (29 mg, 0.299 mmol), SPhos-Pd-G2 (14 mg, 0.020 mmol) in dioxane(9.0 mL) was degassed and purged with N₂ (×3), and then stirred at 90°C. for 30 hours under N₂ atm. Upon completion, the reaction mixture wascooled to RT, partitioned between EtOAc (30 mL) and water (15 mL). Theorganic phase was separated, washed with brine (5 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC to afford the title compound (60 mg, crude) as ayellow solid.

Step 6a:4-[5-[4-(dimethylamino)-1-piperidyl]-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanone

To a solution of5-[4-(dimethylamino)-1-piperidyl]-7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(60 mg, 0.120 mmol) in ACN (4.0 mL) was added aq. HCl (6 M, 4 mL). Themixture was stirred at 25° C. for 1 hour. Upon completion, the reactionmixture was adjusted pH to 8 by NaHCO₃, diluted with water (10 mL) andextracted with EtOAc (15 mL×2). Organic layers were combined, washedwith brine (10 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (30 mg, crude) as ayellow solid.

Step 6b:4-[5-[4-(dimethylamino)-1-piperidyl]-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanolhydrochloride

To a solution of4-[5-[4-(dimethylamino)-1-piperidyl]-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanone(30 mg, 0.066 mmol) in McOH (1.0 mL) was added NaBH₄ (2.5 mg, 0.066mmol). The mixture was stirred at −40° C. for 0.5 hour. Upon completion,to the reaction mixture was added with sat. aq. NaHCO₃(5 mL), extractedwith EtOAc (5 mL×2). The organic layers were combined, washed with brine(5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by prep-HPLC. The eluent was concentrated toremove organic solvent, treated with aq. HCl (0.1 M, 2 mL), andlyophilized to give the title compound (1.2 mg, 3.6% yield, 97% purity)as a red solid. The structure and purity of the title compound wereconfirmed by LCMS and ¹H NMR.

Example 5: Synthesis of Compound 116

Compound 116 (as shown in FIG. 1) was synthesized according to GeneralScheme 1, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 4: (S)-tert-butyl4-(2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(60 mg, 0.133 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(82 mg, 0.266 mmol), Na₂CO₃ (42.3 mg, 0.399 mmol), Pd(dppf)Cl₂CH₂Cl₂(5.4 mg, 0.0067 mmol) in DME (3 mL) and H2O (1 mL) was degassed andpurged with N₂ for 3 times, and then stirred at 90° C. for 2 hours underN₂ atm. Upon completion, the reaction mixture was diluted with EtOAc (20mL), and then extracted with EtOAc (20 mL×3) and water (20 mL). Theorganic layers were combined, washed with brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC to give the tittle compound (50 mg, 0.087 mmol, 66%yield, 96% purity) as a yellow solid Step 5: (S)-tert-butyl4-(2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-[7-(1,4-dioxaspiro[4.5]decan-8-yl)-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(50 mg, 0.090 mmol) in McOH (10 mL) was added Pd/C (5% purity, 30 mg)under N₂. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2 (15 psi) at 25° C. for12 hours. Upon completion, the reaction mixture was filtered andconcentrated in vacuo to give a mixture of the desired product andover-reduced byproduct (35 mg in total, crude). To a solution of themixture (35 mg, 0.063 mmol) in DCM (5 mL) was added MnO₂ (27 mg, 0.314mmol). The mixture was stirred at 25° C. for 12 hours. Upon completion,the reaction mixture was filtered and concentrated in vacuo. The residuewas purified by prep-TLC to give the tittle compound (18 mg, 52% yield)as a yellow solid.

Step 6a:(S)-4-(2-(heptan-2-ylamino)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

To a solution of tert-butyl4-[7-(1,4-dioxaspiro[4.5]decan-8-yl)-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]piperidine-1-carboxylate(45 mg, 0.081 mmol) in MeCN (3 mL) was added aq. HCl (6 M, 3 mL). Themixture was stirred at 25° C. for 30 minutes. Upon completion, thereaction mixture was added NaHCO₃ to adjust pH to 6-7, and thenextracted with EtOAc (20 mL×3). Organic layers were combined, washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (40 mg, crude).

Step 6b: (1S,4r)-4-(2-((S)-heptan-2-ylamino)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolhydrochloride

To a solution of4-[2-[[(1S)-1-methylhexyl]amino]-5-(4-piperidyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexanone(40 mg, 0.097 mmol) in McOH (5 mL) was added NaBH₄ (15 mg, 0.389 mmol).The mixture was stirred at 0° C. for 30 minutes. Upon completion, thereaction mixture was quenched by aq. sat. NH₄Cl (20 mL) at 0° C., thendiluted with EtOAc (30 mL), and extracted with EtOAc (30 mL×3). Organiclayers were combined, washed with brine (20 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep-HPLC. The eluent was concentrated to remove organic solvent, thentreated with aq. HCl (0.2M, 0.5 mL) and lyophilized to give the titlecompound (19.4 mg, 44% yield, 99% purity) as HCl salt as a yellow solid.The structure and purity of the title compound were confirmed by LCMSand ¹H NMR.

Example 6: Synthesis of Compound 111

Compound 111 (as shown in FIG. 1) was synthesized according to GeneralScheme 2, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 1: (S)-ethyl2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylate

To a solution of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-N-[(1S)-1-methylhexyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine(0.1 g, 0.22 mmol) in EtOH (15 mL) was addedcyclopentyl(diphenyl)phosphane:iron (0.06 g, 0.11 mmol),benzonitrile:dichloropalladium (0.02 g, 0.055 mmol) and TEA (0.09 mL,0.66 mmol). The suspension was degassed and purged with CO for severaltimes. The mixture was stirred under CO (3 MPa) at 130° C. for 48 hours.The reaction mixture was cooled to RT and concentrated in vacuo. Theresidue was partitioned between EtOAc (30 mL) and water (20 mL) andseparated. The aqueous layer was extracted with EtOAc (25 mL×2). Allorganic layers were combined, washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep-TLC to afford the title compound (0.08 g, 82% yield) as a yellowoil.

Step 2:(S)-2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylicacid

To a solution of (S)-ethyl2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylate(0.08 g, 0.18 mmol) in McOH (4 mL) was added aq. NaOH (4 M, 2 mL). Themixture was stirred at 45° C. for 3 hours. The reaction mixture wasquenched by addition HCl (1 M) and adjusted pH to 2. The resultingmixture was then diluted with water (10 mL) and extracted with EtOAc (10mL×3). All organic layers were combined, washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC to afford the title compound (0.04 g, 58% yield) asa yellow solid.

Step 3:(S)—N-(4-fluorophenyl)-2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

To a solution of(S)-2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylicacid (0.04 g, 0.096 mmol) in DMF (2 mL) was added HATU (0.04 g, 0.12mmol). The mixture was stirred at 60° C. for 0.5 hour, before treatedwith DIPEA (0.05 g, 0.38 mmol, 0.067 mL) and 4-fluoroaniline (0.013 g,0.012 mmol). The resulting mixture was then stirred at 60° C. foranother 0.5 hour then cooled to RT. The mixture was diluted with water(10 mL) and extracted with EtOAc (10 mL×3). All organic layers werecombined, washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC to affordthe title compound (21 mg, 32% yield, 75% purity) as a yellow oil.

Step 4a:N-(4-fluorophenyl)-2-[[(1S)-1-methylhexyl]amino]-7-(4-oxocyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

To a solution of(S)—N-(4-fluorophenyl)-2-(heptan-2-ylamino)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide(21 mg, 0.031 mmol) in DCM (1 mL) was added TFA (0.38 mL, 5.1 mmol). Themixture was stirred at RT for 3 hours.

The reaction mixture was quenched by sat. aq. NaHCO₃ solution (5 mL),then extracted with DCM (5 mL×3). Organic layers were combined, washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-TLC to afford the title compound(15 mg, 92% yield, 88% purity) as a yellow solid.

Step 4b:N-(4-fluorophenyl)-7-(4-hydroxycyclohexyl)-2-[[(1S)-1-methylhexyl]amino]pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

To a solution ofN-(4-fluorophenyl)-2-[[(1S)-1-methylhexyl]amino]-7-(4-oxocyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide(15 mg, 0.03 mmol) in McOH (1 mL) was added NaBH₄ (2.4 mg, 0.06 mmol) at−40° C. and stirred at −40° C. for 0.5 hour. The reaction mixture wasquenched by water (0.2 mL), and then concentrated in vacuo. The residuewas purified by prep-HPLC. The eluent was concentrated to remove organicsolvent and lyophilized to afford the title product (2.4 mg, 5.6% yield,98% purity) as a yellow solid. The structure and purity were confirmedby LCMS and ¹H NMR.

Example 7: Synthesis of Compound 124

Compound 124 (as shown in FIG. 1) was synthesized according to GeneralScheme 3, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 6:trans-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol

A mixture of4-(5-bromo-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-o((134mg, 0.358 mmol), NaHCO₃(103 mg, 1.23 mmol), and 1-Methyl-4-[4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine (115 mg, 0.346mmol) was suspended in 1,4-Dioxane (3.6 mL) and H2O (1.2 mL) and themixture was degassed by bubbling N₂ through the mixture for 5 min. Themixture was treated with[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(11) (17.9 mg,0.0219 mmol) and then heated at 90° C. for 30 min. The reaction mixturewas cooled to RT and poured into H2O and extracted with EtOAc (×3). Thecombined organic layers were washed with 1-120, brine sequentially,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theaqueous phase was basified by aq. Na₃H (1 M) and extracted with DCM(×3). The combined layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was taken up inMeOH and absorbed onto 2.5 g of Silicycle SCX functionalized silica. Thepad was washed with MeOH (ca. 30 mL) and the product was eluted with NH3in McOH (7M). The fractions containing the product were concentrated togive an orange residue which was used directly without furtherpurification (153 mg, 88%)

Step 7:trans-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol

To a microwave tube was addedtrans-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol(50.0 mg, 0.103 mmol) (mixture of cis/trans diastereoisomers), NMP(0.104 mL), DIPEA (0.046 mL, 0.258 mmol) and (S)-1-Methoxy-2-propylamine(93.1 mg, 1.03 mmol). The resulting mixture was heated at 160° C. undermicrowave irradiation for 3 hours. The reaction mixture was partitionedbetween EtOAc and water and separated. The aqueous layer was extractedwith EtOAc (×2). All organic layers were combine, washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by preparative HPLC to give the title compound (14mg, 27%) as a single diastereomer. The structure and purity wereconfirmed by LCMS and ¹H NMR.

Example 8: Synthesis of Compound 122 (as shown in FIG. 1)

Step 1: ethyl4-(2-((8)-heptan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylate

To a solution of ethyl4-(2-((S)-heptan-2-ylamino)-7-(4-oxocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylate(54.0 mg, 112 μmol) in McOH (3.00 mL) was added sodium borohydride (17.7mg, 449 μmol) at 0° C. The resulting mixture was stirred at 0° C. for 1hour. Upon completion, 1M HCl and EtOAc were added. The aqueous layerwas extracted 3 times with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the tittle compound (50 mg, crude) as a yellowsolid.

Step 2:4-(2-((S)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylicAcid

To a solution of ethyl4-(2-((S)-heptan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylate(50.0 mg, crude) in EtOH (2.30 mL) was added sodium hydroxide (1M) (2.30mL, 2.30 mmol). The resulting mixture was stirred at RT for 2.5 hours.Upon completion, 1M HCl and EtOAc were added. The aqueous layer wasextracted 3 times with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC with AmF/ACN (ammoniumformate/acetonitrile) and lyophilized to give4-(2-((S)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylicacid (3.2 mg, 6.8%) as a yellow solid. The structure and purity of thetitle compound was confirmed by ¹H NMR and LCMS.

Example 9: Synthesis of Compounds 125 and 109 (as Shown in FIG. 1)

Step 1: (S)-ethyl4-(2-(heptan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylate

Ethyl4-(2-((5-heptan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylatewas synthesized according to general procedure 1 using ethyl 4 (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate. To asolution of ethyl4-(2-((S)-heptan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohex-3-enecarboxylate(245 mg, 508 μmol) in McOH (12.3 mL) was added palladium on activatedcarbon (120 mg). The resulting mixture was purged with hydrogen threetimes and was then stirred at RT for 15 hours. Upon completion, thereaction material was filtered and concentrated under reduced pressureto give (5)-ethyl4-(2-(heptan-2-ylamino)-7-(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylate(195 mg, crude).

To a solution of (5)-ethyl4-(2-(heptan-2-ylamino)-7-(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylate(534 mg, crude) in THF (16.2 mL) was added activated manganese(IV) oxide(102 mg, 1.20 mmol). The resulting mixture was stirred at 50° C. for 1hour. Upon completion, the reaction material was filtered over Celite®with EtOAc and concentration under reduced pressure to give the titlecompound (565 mg, crude).

Step 2:(cis)-4-(2-((S)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylicacid

To a solution of (5)-ethyl4-(2-(heptan-2-ylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylate(565 mg, crude) in EtOH (26 mL) was added sodium hydroxide (1M) (26 mL,26 mmol). The resulting mixture was stirred at RT for 16 hours. Uponcompletion, 1M HCl and EtOAc were added. The aqueous layer was extracted3 times with EtOAc. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-HPLC with AmF/ACN and lyophilized to give(cis)-4-(2-((5)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylicacid (90 mg) as a yellow solid. The structure and purity of the titlecompound was confirmed by ¹H NMR and LCMS.

Step 3:((cis)-4-(2-((S)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexyl)(morpholino)methanone

To a solution of(cis)-4-(2-((5)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexanecarboxylicacid (30.0 mg, 65.7 μmol) N,N-diisopropylethylamine (57.8 μL, 328 μmol)and morpholine (29.0 μL, 328 μmol) in dry DMF (1.50 mL) was added HATU(25.8 mg, 65.7 μmol). The resulting mixture was stirred at RT for 2hours. Upon completion, water and EtOAc were added. The aqueous layerwas extracted 3 times with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography onC18 silica with AmF/ACN and lyophilized to give((cis)-4-(2-((5)-heptan-2-ylamino)-7-((trans)-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)cyclohexyl)(morpholino)methanone(23 mg, 67%) as a yellow solid. The structure and purity of the titlecompound was confirmed by ¹H NMR and LCMS.

Example 10: Synthesis of Compound 127

Compound 127 (as shown in FIG. 1) was synthesized using the procedure ofExample 9 and N-methylpiperazine.

Example 11: Synthesis of Compound 137

Compound 137 (as shown in FIG. 1) was synthesized using the procedure ofExample 9 and thiomorpholine 1,1-dioxide.

Example 12: Synthesis of Compounds 131 and 132 (as shown in FIG. 1)

Step 1:(S)-4-(5-bromo-2-(sec-butylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

To a solution of(S)-5-bromo-N-(sec-butyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(567 mg, 1.39 mmol) in MeCN (25 mL) was added HCl (6 M, 17 mL). Themixture was stirred at 25° C. for 1 hour. Upon completion, the reactionmixture was adjusted with NaHCO₃ to pH=6-7, then extracted with Eta)Ar(600 mL×3) and water (600 mL). The combined organic layers were driedover anhydrous MgSO₄, filtered and concentrated in vacuo to give 501 mgof(S)-4-(5-bromo-2-(sec-butylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone(99% yield). The material was subsequently used “as is.”

Step 2:(S)-4-(2-(sec-butylamino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

To a solution of(S)-4-(5-bromo-2-(sec-butylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone(140 mg, 384 μmol), sodium hydrogenocarbonate (97 mg, 1.15 mol) and1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine(127.6 mg, 384 μmol) in dioxane (3.8 mL)/water (1.2 mL) was degassedwith nitrogen. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(11) (18.8 mg, 23 μmol)was then added and the resulting mixture was stirred at 90° C. undernitrogen for 2 hours. Upon completion, water and EtOAc were added. Theaqueous layer was extracted 3 times with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica (5/5 hexanes/EtOAc to 100% EtOAc, then 9/1 to5/5 EtOAc/MeOH with 1% of Et₃N) to give the title compound (126 mg,69%).

Step 3:(cis)-4-(2-((S)-sec-butylamino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanoland(trans)-4-(2-((S)-sec-butylamino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol

To a solution of(S)-4-(2-(sec-butylamino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone(86.0 mg, 181 μmol) in dry THF (3 mL) was added methyl lithium (200 μL,320 μmol) under nitrogen at 0° C. The resulting mixture was stirred at0° C. After 10 minutes, methyl lithium (100 μL, 160 μmol) were added.After 10 minutes, water and EtOAc were then added. The aqueous layer wasextracted 3 times with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was again treated with MeLi and worked up,as above. This process was carried out a third time. The residue waspurified by prep HPLC with AmF/ACN. The two diastereoisomers wereseparated and lyophilized, leading to(cis)-4-(2-((S)-sec-butylamino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol(10 mg, 11%) and(trans)-4-(2-((S)-sec-butylamino)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol(18 mg, 20%) as yellow solids.

Example 13: Synthesis of Compounds 204 and 205 (as Shown in FIG. 1)

The mixture of diastereoisomers was obtained from intermediate T usinggeneral procedure 4 and4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine. Thediastereosiomers were separated by chiral HPLC using ChiralPak IB, 250mm×4.6 mm ID, 5 μm with 7.5:2.5:90 MeOH:DCM:hexane (1 mL/min, 45 bars,26° C., 20 min).

Example 14: Synthesis of Compounds 211 and 212 (as Shown in FIG. 1)

Compounds 211 and 212 were synthesized using the procedure of Example 13using racemic 4-methoxybutan-2-amine and the diastereomers separated ona chiral column.

Example 15: Synthesis of Compounds 156 and 157 (as Shown in FIG. 1)

The mixture ix of diastereoisomers was obtained from intermediate Eusing general procedure 4 and racemic4-(1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)morpholine.The diastereosiomers were separated by chiral HPLC using ChiralPak IA,250 mm×4.6 mm ID, 5 μm with 2:16:82 MeOH:i-PrOH:hexane (0.8 mL/min, 45.5bars, 26° C., 25 min).

Example 16: Synthesis of Compound 228 (as Shown in FIG. 1)

Step 1. Methyl5-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)picolinate

A mixture of(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol(527 mg, 1.37 mmol), (6-(Methoxycarbonyl)pyridin-3-yl)boronic acid (1.06g, 5.88 mmol) and sodium hydrogenocarbonate (137 μL, 3.52 mmol) indioxane and H2O (2.11 mL) was degassed by bubbling N₂ through themixture for 5 min. The mixture was then treated with PdCl₂dppf (102 mg,137 μmol) and heated at 80° C. After heating for 1 h the reaction wastreated with 0.5 equiv boronate, and 1 equiv (NaHCO₃). The reaction wasallowed to heat overnight. The mixture was cooled to RT and then pouredinto H2O, diluted with EtOAc, and filtered through Celite®. The layerswere separated and the aq. phase was extracted with EtOAc (×3). Thecombined organic layers were washed (H2O, brine), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by column chromatography(Combiflash, 10 g column, 0 to 30% IPA in DCM). we obtained ayellow-orange foam (142 mg).

Step 2:5-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)picolinicacid

A mixture of methyl5-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)picolinate(135 mg, 307 μmol) in McOH (4 mL) at RT was treated with NaOH (2 mL, 2mmol) and the mixture was allowed to stir at RT for 30 min. A further0.5 mL of NaOH was added and stirring continued for 30 min. The mixturewas acidified with HCl (6M) and concentrated to dryness (evaporated fromtoluene ×2). The residue was used “as is” in the next experiment.

Step 3:5-(7-((1r,45)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-isopropylpicolinamide

The crude product obtained above was suspended in DMF, treated withHunig's base (100 μL) and separated into three 4 mL vials. The reactionswere treated with the amines (isopropylamine 30 mg), followed by HATU(154 mg, 0.40 mmol). After stirring at RT for 30 min, the reactions werediluted with H₂O and extracted with EtOAc (×3). The combined organiclayers were washed (H₂O, brine), dried (Na₂SO4) and concentrated invacuo. The residue was purified by column chromatography (Combiflash, 10g column; DCM-IPA) to give the title compound as a yellow solid (35.8mg, 76%).

Example 17: Synthesis of Compound 223 (as Shown in FIG. 1)

The starting material,3-(7((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzaldehydewas prepared according to step 1 Example 16, using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde as thecoupling partner. The aldehyde so obtained (70.0 mg, 171 μmol) wasdissolved in thy DCM (3 mL) with 3,3-difluoropyrrolidine hydrochloride(50.2 mg, 343 μmol) and then Titanium(IV) isopropoxide (254 μL, 857μmol) was added. The resulting mixture was stirred for 1.5 hours beforethe addition of NaBH(OAc)₃ (93.2 mg, 428 μmol). The reaction was thenstirred 10 more hours. The reaction was quenched by adding McOH (1 mL)and then silica powder (about 4 mL) and stirred for 30 minutes beforebeing concentrated to dryness in vacuo. The material was purified byflash chromatography (20 g) silica column, eluting with DCM:20% IPA inDOA and then by reverse phase on a 12 g C-18 column eluting with solventA=10 μM ammonium formate (AMF) and solvent B=ACN. We obtained the titlecompound as a fluffy solid (35.2 mg, 41%).

Example 18: Synthesis of Compound 135 (as Shown in FIG. 1)

Step 1: (S)-tert-butyl4-(2-(sec-butylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

(S)-4-(5-bromo-2-(sec-butylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(383 mg, 1.04 mmol), tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(461 mg, 1.46 mmol), Pd(dppf)Cl₂ (77.4 mg, 0.104 mmol) and Na₂CO₃ (332mg, 3.12 mmol) were all added to a microwave vial under nitrogen. Then amixture of degassed (by sparging) dioxane (14.4 mL) and H2O (4.79 mL)was added to the vial and then the mixture was stirred at 80° C.overnight under N₂atm. Upon completion, the reaction mixture was dilutedwith DCM (100 mL) and water (100 mL) and the layers separated. The aq.phase was extracted with DCM (100 mL×3) and the combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuo. Theresidue was purified by flash chromatography using 0-60% EtOAc inhexanes to give 410 mg of the desired compound in 84% yield.

Step 2: (S)-tert-butyl4-(2-(sec-butylamino)-7-(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate

(S)-tert-butyl4-(2-(sec-butylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(320 mg, 0.681 mmol) was dissolved in McOH (16.5 mL). Then, Pd/C (10 wt% loading, 145 mg) was added to the reaction. The reaction was thendegassed and put under 1 atm of hydrogen. This was cycled several timesand then, the reaction was left to stir under 1 atm of hydrogen tillLC-MS showed complete conversion to the desired product. The reactionwas then filtered over Celite® and concentrated in vacuo. The residuewas purified using 0-100% of 1:1 mixture of DCM:hexanes with 10%isopropanol in 1:1 mixture of DCM:hexanes to give 120 mg of the desiredproduct in 37% yield.

Step 3: (S)-tert-butyl4-(2-(sec-butylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate

(S)-tert-butyl4-(2-(sec-butylamino)-7-(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate(120 mg, 0.253 mmol) was dissolved in THF (10.0 mL). Activated manganese(IV) oxide (100 mg, 1.01 mmol) was added and then reaction was stirredat 50° C. till full conversion was observed. Then the reaction wascooled and filtered over Celite® and concentrated in vacuo. This gave108 mg of the desired product in 90% yield. It was then used crude inthe next step.

Step 4:(trans)-4-(2-((S)-sec-butylamino)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

(S)-tert-butyl4-(2-(sec-butylamino)-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate(40 mg, 0.0848 mmol) was dissolved in DCM (5.0 mL) and then a 4 Msolution of HCl in dioxane was added. The reaction was run till fullconversion was observed and then concentrated in vacuo. After, it wasconcentrated and then the residue from this reaction was purified byprep-HPLC (column: XBridge Prep C18 OBD 30×50 mm, 5 μm; mobile phase: 10mM AMF buffer-MeCN; B %: 10%-30%,13 min). The eluent was concentrated toremove organic solvent and the residual aqueous solution was lyophilizedto give 6.5 mg of(trans)-4-(2-((S)-sec-butylamino)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolin 21% yield.

Example 19: Synthesis of Compound 136 (as Shown in FIG. 1)

(trans)-4-(2-((S)-sec-butylamino)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(44 mg, 0.118 mmol) was dissolved in NMP (1.0 mL) in a microwave vialthen 2-chloro-4-methylpyrimidine (15.2 mg, 0.118 mmol) and DIPEA (0.025mL, 0.142 mmol) was added. The reaction was then heated to 100° C.overnight. The reaction was then allowed to cool and then it waspurified by reverse phase chromatography using 0-100% MeCN in H2O (with10 mM AMF). The organic solvent was removed under vacuum, and theaqueous phase was lyophilized to give 26.7 mg of(trans)-4-(2-((S)-sec-butylamino)-5-(1-(4-methylpyrimidin-2-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol in 49% yield.

Example 20: Synthesis of Compound 150-1 (as Shown in FIG. 1)

Step 1: tert-butyl4-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)piperazine-1-carboxylate

(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(250 mg, 0.652 mmol), tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate(359 mg, 0.848 mmol), Pd(dppf)Cl₂ (24.2 mg, 0.0326 mmol) and Na₂CO₃ (207mg, 1.96 mmol) were all added to a microwave vial under nitrogen. Then amixture of degassed (by sparging) dioxane (6.18 mL) and water (1.95 mL)was added to the vial and then the mixture was stirred at 80° C.overnight under N₂ atm. Upon completion, the reaction mixture wasdiluted with DCM (100 mL) and extracted with DCM (100 mL×3) and water(100 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under vacuum. The residue from this reaction waspurified by flash chromatography using 0-50% McOH in DCM to give 223 mgthe desired product in 59% yield.

Step 2:(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(piperazin-1-ylmethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

tert-butyl4-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)piperazine-1-carboxylate(223 mg, 0.385 mmol) was dissolved in DCM (15 ml). Then a 4 M HCl indioxane (4 mL, large excess) was added to the reaction and then thereaction was stirred till complete consumption of starting material wasobserved. It was then concentrated in vacuo. Then it was dissolved in 10mL of EtOH and a large excess of K₂CO₃ was added. This was stirred tillpH=7 was achieved then the solid was filtered and then organic layer wasconcentrated to give 173 mg of(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(piperazin-1-ylmethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolin 94% yield of a yellow solid. The structure and purity of the titlecompounds were confirmed by 41 NMR and LCMS.

Example 21: Synthesis of Compound 150 (as Shown in FIG. 1)

Acetic acid (0.07 mL, 0.125 mmol), HATU (73.7 mg, 0.188 mmol) and DIPEA(0.09 mL, 0.501 mmol) was dissolved in DMF (6.0 mL) and stirred for 30min.(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(piperazin-1-ylmethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(60 mg, 0.125 mmol) was added to the mixture and this was stirredovernight at RT. Full conversion was observed and then this mixture wasdirectly placed onto a 30 gram C18 column and purified using 0-100% MeCNin a 10 mM ammonium bicarbonate (AmB) buffer. The organic solvent wasremoved and the aqueous phase was lyophilized to give 29.7 mg of(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(piperazin-1-ylmethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolin 46% yield. The structure and purity of the title compounds wereconfirmed by 41 NMR and LCMS.

Example 22: Synthesis of Compound 154 (as Shown in FIG. 1)

(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(piperazin-1-ylmethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(25 mg, 0.0522 mmol), 2-Cholo-4-methylpyrimidine (6.71 mg, 0.0522 mmol)and DIPEA (0.01 mL, 0.0627 mmol) was dissolved in NMP (1.0 mL). This washeated to 100° C. overnight. Then, full conversion was observed todesired product. Then the mixture was placed directly on a reverse phasecolumn and the desired product was purified using 0-100% MeCN in a 10 mMAMF buffer. The organic solvent was removed under vacuo. Then, theaqueous layer was lyophilized to give 5.3 mg of(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-((4-(4-methylpyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolas a formate salt in 18% yield. The structure and purity of the titlecompounds were confirmed by ¹H NMR and LCMS.

Example 23: Synthesis of Compound 163 (as Shown in FIG. 1)

(cis)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(70 mg, 0.183 mmol), 4-(Morpholinomethyl)phenylboronic acid (56.5 mg,0.256 mmol), Pd(dppf)Cl₂ (6.77 mg, 0.00913 mmol) and Na₂CO₃ (58.1 mg,0.548 mmol) were all added to sealed tube under nitrogen. Then a mixtureof degassed (by sparging) dioxane (2.63 mL) and water (0.875 mL) wasadded to the sealed tube and then the mixture was stirred at 80° C. forovernight under N₂ atm. Upon completion, the reaction mixture wasdiluted with DCM (30 mL) and extracted with DCM (30 mL×3) and water (30mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue from this reaction was purifiedby normal phase chromatography using 0-100% iPrOH in DCM. The purefractions were concentrated to give 32.1 mg of(cis)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolin 37% yield. The structure and purity of the title compounds wereconfirmed by 41 NMR and LCMS.

Example 24: Synthesis of Compounds 175 and 176 (as Shown in FIG. 1)

To a solution of(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(2-methylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(40.0 mg, 101 μmol) in DMF (800 μL) was added potassium tert-butoxide(1M in THF) (253 μL, 253 μmol) at RT under nitrogen. The mixture wasstirred for 10 min. Iodomethane (6.30 μL, 101 μmol) was then added at 0°C. and the resulting mixture was stirred at 0° C. for 2 hours. Uponcompletion, water and EtOAc were added. The aqueous layer was extractedthree times with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica with DCM/MeOH to give(trans)-4-(2-(((S)-1-methoxypropan-2-yl)(methyl)amino)-5-(2-methylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(14 mg, 34%) and7-((trans)-4-methoxycyclohexyl)-N—((S)-1-methoxypropan-2-yl)-N-methyl-5-(2-methylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(10 mg, 24%) as yellow solids.

Example 25: Synthesis of Compound 187 (as Shown in FIG. 1)

The starting material,4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzoicacid was prepared according to step 1 of Example 8, using4-Carboxylphenylboronic acid pinacol ester as the coupling partner. Thebenzoic acid so obtained, (80.0 mg, 0.188 mmol), HATU (111 mg, 0.283mmol) and DIPEA (0.133 mL, 0.754 mmol) was dissolved in DMF (10.0 mL)and stirred for 30 min. Then morpholine (0.02 mL, 0.226 mmol) was addedto the mixture and this was stirred overnight at RT. Full conversion wasobserved and then this mixture was concentrated in vacuo and placeddirectly onto a 25 g silica column and purified using 0-100% iPrOH inDCM. The fractions containing the desired product were concentrated. Theproduct was contaminated with DIPEA. The product was then re-purified(loaded using a few drops of TFA) using a 0-100% MeCN in a 10 mMammonium formate buffer. The fractions containing the desired productwere combined and made basic using solid potassium carbonate. Then themixture was extracted several times with DCM till no more product wasfound in the aqueous layer. The organic solvent was removed and then theproduct was lyophilized to give 25.4 mg of(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)(morpholino)methanonein 27% yield.

Example 26: Synthesis of Compound 129 (as Shown in FIG. 1)

The starting material,(S)-4-(2-(sec-butylamino)-5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol was prepared according to step 1 ofExample 10, using 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester asthe coupling partner. Then,(S)-4-(2-(sec-butylamino)-5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(80.0 mg, 0.216 mmol), Pd/C (46 mg, 10% wt on carbon) were dissolved inMcOH (5.22 mL). Then, the mixture was degassed and put under 1 atm ofhydrogen several times. It was left to stir under 1 atm of hydrogen tillcomplete conversion to the desired product was observed by LC-MS. It wasthen filtered over Celite® and concentrated in vacuo. The residue fromthis reaction was purified by prep-HPLC (column:)(Bridge Prep C18 OBD30×50 mm, 5 μm; mobile phase: 10 mM AMF buffer-MeCN; B %: 35%-45%,13min). The eluent was concentrated to remove organic solvent and theresidual aqueous solution was lyophilized to give 18.4 mg of(trans)-4-(2-((S)-sec-butylamino)-5-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanolin 23% yield. The structure and purity of the title compounds wereconfirmed by ¹H NMR and LCMS.

Example 27: Synthesis of Compound 229 (as Shown in FIG. 1)

A solution ofcis-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol(350 mg, 913 μmol) and PPh₃ (363 mg, 1.37 mmol) in 2-Me-THF (4.67 mL)was cooled to OC and treated with N,N-Diisopropylethylamine (240 μL,1.37 mmol) followed by diisopropyl azodicarboxylate (DIAD; 275 μL, 1.37mmol). After stirring for 45 min, the mixture was treated withdiphenoxyphosphoryl azide (DPPA 304 μL, 1.37 mmol) and allowed to warmto RT while stirring overnight. Triphenylphosphine (363 mg, 1.37 mmol)was added and the mixture allowed stir at RT overnight. The mixture wasthen treated with H₂O (200 μL) and was allowed to stir at 50° C.overnight. The reaction was concentrated and the residue was purified bycolumn chromatography (silica gel, 25 g column, 0 to 30% MeOH in DCM).We obtained a yellow solid 127 mg.

Example 28: Synthesis of Compounds 248 and 250 (as Shown in FIG. 1)

Step 1:((trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-((triethylsilyl)ethynyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

In a flame dried and inert gas purged microwave vial was added(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(60.0 mg, 157 μmol) and TEA (1 mL) and THF (1 mL). The solution waspurged with N₂ under sonication for 8 minutes. Then the(Triethylsilyl)acetylene (58.1 μL, 313 μmol) was added, followed by1,1-bis(diphenylphosphino)ferrocene-palladium dichloride (11.6 mg, 15.7μmol) and copper(I) iodide (6.08 mg, 31.3 μmol). Lastly the microwavevial was capped and again, the solution was purged with inert gas undersonication for 8 minutes. The vial was placed in oil bath and heated at90° C. for 15 hours. Upon completion, the reaction mixture was dilutedwith EtOAc (30 mL) and water 30 mL) and then extracted with EtOAc (30mL×3). The organic layers were combined, washed with sat NaHCO₃(30 mL),brine (30 mL×2), dried over anhydrous MgSO₄, filtered and concentrated.The crude residue was purified on a 20 g silica column eluting with (A)DCM and (B) 20%,MeOH in DCM. Title compound obtained as a dark yellowoil (63.0 mg, 91%).

Step 2:(trans)-4-(5-ethynyl-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

((trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-((triethylsilyl)ethynyl) pyrrolo[2,1-f][1,2,4]triazin-7-yl) cyclohexanol (63.0 mg, 142μmol) was dissolved in McOH (3.00 mL) and then finely grinded K₂CO₃(39.3 mg, 285 μmol) was added. The heterogeneous mixture was gentlyheated to 35° C. for 1.5 hour. Upon completion, the solvent was removedin vacuo and the remaining paste was partitioned in a separatory funnelwith water (30 mL) and EtOAc (30 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The organic layers were combined, washed withwater (30 mL), brine (30 mL×2), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give the tittle compound (43 mg, crude) as abeige solid.

Step 3:(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

To a mixture of copper(i) iodide copper(i) iodide (1.25 mg, 6.55 μmol),DIPEA (N,N-diisopropyl ethylamine; 2.29 μL, 13.1 μmol) and acetic acid(0.750 μL, 13.1 μmol) in DCM (1.0 mL) was added(trans)-4-(5-ethynyl-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]Triazin-7-yl)cyclohexanol (43.0 mg, 131 μmol)and trimethylsilylmethyl azide (25.3 μL, 170 μmol) at RT. The resultantmixture was stirred for 15 hours. Upon completion the reaction mixturewas concentrated in vacuo. The product was purified on a 20 g silicacolumn eluting with 5 to 10% Hexane:MTBE to afford title compound as awhite solid (42.0 mg, 70% yield).

Step 4:(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

Product(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(42.0 mg, 91 μmol) was dissolved in THF (2 mL) followed by the additionof TBAF [1N THF] (184 μL, 184 μmol). Upon completion, the solvent wasremoved in vacuo and the remaining crude was partitioned in a separatoryfunnel with water (30 mL) and EtOAc (30 mL). The aqueous layer wasextracted with EtOAc (30 mL×3). The organic layers were combined, washedwith water (30 mL), brine (30 mL×2), dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The crude product was purified on a30 g C-18 column eluting with (A) water 10 μmol AMF buffer and (B) ACN.The eluent was concentrated to remove organic solvent and thenlyophilized to give title compound (35 mg, 40% yield) as a light yellowsolid.

Example 29: Synthesis of Compound 192 (as Shown in FIG. 1)

In a flame dried microwave vial and purged with inert gas was quicklyintroduced the Cs₂CO₃ (128 mg, 391 μmol) and the(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(50.0 mg, 130 μmol) and the amide morpholin-3-one (40.8 mg, 391 μmol).The dry NMP (1.50 mL) was added though the septum followed by the(1R,2R)-dimethylcyclohexane-1,2-diamineamine (10.6 μL, 65.2 μmol). Theresulting mixture was degassed for 8 minutes under sonication and thenthe copper(I) iodide (5.07 mg, 26.1 μmol) was added. The reaction heatedfor 15 hours at 120° C. Upon completion, the solvent was removed invacuo and the remaining crude was partitioned in a separatory funnelwith water (30 mL) and EtOAc (30 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The organic layers were combined, washed withwater (30 mL), brine (30 mL×2), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was purified on a 30 g C-18column eluting with water containing 10 mM AMF and ACN. The eluent wasconcentrated to remove organic solvent and then lyophilized to givetitle compound (24 mg, 47% yield, 99% purity) as light yellow solids.

Example 30: Synthesis of Compound 177 (as Shown in FIG. 1)

In a microwave vial purged with inert gas, were added(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl) amino) pyrrolo[2,1-f][1,2,4]triazin-7-yl) cyclohexanol (70.0 mg, 183 μmol),pyrrolidinone (37.7 mg, 438 μmol), cesium carbonate (83.9 mg, 256 μmol),1,4-dioxane (2.00 mL) and water (1.60 mL). The resulting mixture wasdegassed by inert gas bubbling. In parallel, in a 2 dram vial purgedwith inert gas was added tris(dibenzylideneacetone) dipalladium(O)chloroform adduct (9.45 mg, 9.13 μmol) and4,4-Bis(diphenylphosphino)-9,9-dimethylxanthene (10.8 mg, 18.3 μmol) and1,4-dioxane (1 mL). This solution was added and the solution was purgedwith inert gas under sonication for 5 min and then heated for 5 min inan oil bath at 90° C. for catalyst pre-activation. After 5 min, thecatalyst solution was syringed out and injected into the couplingpartner mix. The solution was heated 15 hours at 105° C. Uponcompletion, the solvent was removed in vacuo. The residue was purifiedby flash chromatography on silica (24 g column) eluting with 0 to 100%DCM:20% IPA in DCM and then on a 12 g C-18 column eluting with watercontaining 10 mM AMF and ACN. The eluent was concentrated to removeorganic solvent and then lyophilized to give title compound (4.5 mg, 6%yield, 98% purity) as light yellow solids.

Example 31: Synthesis of Compound 178 (as Shown in FIG. 1)

The synthesis was carried out using the same protocol as described instep 1 of Example 30 using 2-oxa-6-azaspiro[3.4]octan-7-one as crosscoupling partner. Title compound (7.3 mg, 9% yield, 95% purity) obtainedas a light yellow solid.

Example 32: Synthesis of Compound 266 (as Shown in FIG. 1)

In a vial purged with inert gas, were introduced(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl) amino) pyrrolo[2,1-f][1,2,4]triazin-7-yl) cyclohexanol (80.0 mg, 0.209 mmol), sodiumhydrogenocarbonate (70.2 mg, 0.836 mmol) and the boronate1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl) cyclopropane carbonitrile (307 mg, crude). 1,4-dioxane (2 mL)was added and the system was degassed by evacuating and backfilling 3times with inert gas. In parallel, a second vial was purged with inertgas and water (1.3 mL) was added, and the system degassed as above.CatacXium F sulf (16.2 mg, 0.0209 mmol) and sodiumtetrachloropalladate(II) (3.13 mg, 0.0104 mmol) and sodiumhydrogenocarbonate (10.5 mg, 0.125 mmol) were added and the solution washeated for 1 hour at 60° C. After heating for 1 h, the ligand-palladiumsolution was syringed out and injected into the first vial containingthe coupling partner mix. The resulting solution was heated 15 hours at90° C. Upon completion the crude was diluted with EtOAc (30 mL) andwashed (2×) with NaHCO₃ and then (6×20 mL) of 1N HCl. The organic phasewas set aside and the acid aqueous phase was basified with K2CO₃ andextracted with EtOAc (3×20 mL) and 2-Methyl THF (3×20 mL). The organicphase was dried with Na₂SO₄ filtered and then concentrated in vacuo. Theproduct was purified on 30 g C-18 column and eluted with water 10 mM AMFand ACN. The eluent was concentrated to remove organic solvent. Theproduct was extracted with EtOAc and sat NaHCO₃. The organic layers werecombined, dried over anhydrous MgSO₄, filtered and concentrated invacuo. The residue was frozen and then lyophilized to give titlecompound (53 mg, 57% yield) as a light yellow solid.

Example 33: Synthesis of Compound 331

Compound 331 (as shown in FIG. 1) was synthesized according to GeneralScheme 6, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 2:(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

In a flame-dried flask was added dry DMSO (5.42 mL) which was degassedwith argon for 10 min (bubbling with a long needle, in a sonicationbath). Potassium acetate (349 mg, 3.52 mmol), palladium(II) acetate(13.3 mg, 58.7 μmol) and tricyclohexylphosphine tetrafluoroborate (43.7mg, 117 μmol) were then added and the reaction mixture was degassedagain for 10 min and then stirred at RT for 20 min.(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(450 mg, 1.17 mmol) and Bis(pinacolato)diboron (913 mg, 3.52 mmol) werethen added and the resulting mixture was stirred overnight at 90° C.Upon completion, water and EtOAc were added. The aqueous layer wasextracted three times with EtOAc. The combined organic layers werewashed with sat. NH₄C₁, sat. NaHCO₃ and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica with DCM/IPA to give titlecompound (385 mg, 69% yield) as a light yellow solid.

Step 3: Methyl2-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-1-yl)-2-methylpropanoate

To a microwave vial was added(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(385 mg, 895 μmol), methyl 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoate(605 mg, 2.06 mmol) and cesium carbonate (741 mg, 2.24 mmol), followedby DME (8.94 mL) and water (3.89 mL). The resulting mixture was set to 3cycles of vacuum and argon sparging and XPhos(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) PalladacycleGen. 4 (31.4 mg, 35.8 μmol) was then added. The resulting mixture washeated at 90° C. for 10 min under microwave irradiation. Uponcompletion, water and DCM were added. The aqueous layer was extractedthree times with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silicawith DCM/MeOH to give title compound (330 mg, 78% yield) as a yellowsolid.

Step 4:2-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-1-yl)-2-methylpropanoicAcid

To a solution of methyl2-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-1-yl)-2-methylpropanoate(330 mg, 701 μmol) in McOH (15.6 mL) was added sodium hydroxide (1 M inwater) (16 mL, 96.1 mmol). The resulting mixture was stirred at RT for 3hours. Upon completion, HCl (1M in water) and EtOAc were added. Theaqueous layer was extracted six times with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound (321 mg,crude) as an orange solid.

Step 5:1-(1,1-dioxidothiomorpholino)-2-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-one

To a solution of2-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid (50.0 mg, 110 μmol), thiomorpholine-1,1-dioxide (37.0 mg, 274 μmol)and N,N-diisopropylethylamine (42.2 μL, 241 μmol) in ACN (766 μL), wasadded HATU (51.0 mg, 131 μmol). The resulting mixture was stirred at 55°C. under nitrogen. The residue was purified by flash chromatography onC18 silica with AmF/ACN and lyophilized to give the title compound as ayellow solid. The structure and purity of the title compound wasconfirmed by ¹H NMR and LCMS.

Example 34: Synthesis of Compounds 452 and 453 (as Shown in FIG. 1)

Step 1:4-(5-bromo-2-(methylsulfonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

A solution of5-bromo-2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine(26.0 g, 62.5 mmol) in ACN (400 mL) and acetone (125 mL) was cooled to0° C. and treated with hydrochloric acid (65 mL, 390 mmol) and allowedto stir for 2 hours. The reaction mixture was then poured carefully intoa stirred solution of saturated NaHCO₃ and the mixture was allowed tostir for 20 min. The solution was extracted with EtOAc (×3) and theorganic layers were washed (brine), dried (Na₂SO₄) and concentrated invacuo. The crude material was then dissolved in 75 mL acetone and 75 mLMeCN and treated with 50 mL of HCl 6M at 0° C. After 5 minutes the icebath was removed and the mixture was allowed to stir at RT for 30minutes. The reaction was worked up as above and the crude material(17.92 g) was used as is in the next experiment.

Step 2:(S)-4-(5-bromo-2-((1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

A mixture of5-bromo-2-(methylsulfonyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine(1.00 g, 2.69 mmol), (S)-1-methoxy-2-propylamine (3.12 mL, 29.3 mmol),and N,N-diisopropylethylamine (1.09 mL, 6.21 mmol) in dry DMSO (3.13 mL)was heated at 130° C. for 2 hours. The reaction mixture was cooled to RTand poured into water and extracted 3 times with EtOAc. The combinedorganic layers were washed with brine, water, dried (Na₂SO₄) andconcentrated in vacuo. The crude material was used as in subsequentreactions.

Step 3:(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanoland(cis)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol

A solution of(S)-4-(5-bromo-2-((1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone(300 mg, 787 μmol) in THF (12.0 mL) was cooled to 0° C. and treated withmethylmagnesium bromide (656 μL, 1.97 mmol) dropwise. The solution wasallowed to stir overnight and then treated with sat NH₄C₁. The reactionmixture was poured into water and extracted with EtOAc (×3). Thecombined organic layers were washed (water, brine), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by column chromatography(Combiflash, 10 g column, 0 to 100% solvent A=50:50 DCM:hexanes, andsolvent B=20% IPA in 50:50 DCM:hexanes) to give(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol(66 mg, 21%) and(cis)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol(64 mg, 21%). The relative stereochemistry is unclear at this point andwill be left arbitrary.

Step 4:(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol

A mixture of(trans)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanol(60.0 mg, 151 μmol), sodium hydrogenocarbonate (38 mg, 453 μmol) and1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(83.1 mg, 332 μmol) in dioxane (1.02 mL) and water (339 μL) was degassedby evacuating and backfilling the flash with argon. The residue wastreated with 1,1-bis(diphenylphosphino)ferrocene-palladium dichloride(11.2 mg, 15.1 μmol) and then heated at 80° C. for 4 hours. The reactionmixture was poured into water and extracted with EtOAc (×3). Thecombined organic layers were washed (water, brine), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by column chromatography(Combiflash, 50 g column, 10 to 100% IPA in DCM. The residue wasevaporated from MeCN, and the residue was lyophylized to give the titleproduct as a fluffy yellow solid (15.6 mg, 23%). The structure andpurity was confirmed by ¹H NMR and LCMS.

The diastereoisomer(cis)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-methylcyclohexanolwas obtained using the same procedure.

Example 35: Synthesis of Compound 406 (as Shown in FIG. 1)

A mixture of(S)-4-(5-bromo-2-((1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone(250 mg, 656 μmol), sodium hydrogenocarbonate (165 mg, 1.97 mmol) and1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(361 mg, 1.44 mmol) in dioxane (4.42 mL) and water (1.47 mL) wasdegassed by evacuating and backfilling the flash with argon. The residuewas treated with 1,1-bis(diphenylphosphino)ferrocene-palladiumdichloride (48.6 mg, 65.6 μmol) and then heated at 80° C. for 4 hours.The reaction mixture was poured into water and extracted 3 times withEtOAc. The combined organic layers were washed with water, brine, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by columnchromatography (Combiflash, 50 g column, 10 to 100% IPA in DCM, then 10g C18 column 10 to 90% MeCN in water containing 10 mM AMF) andlyophilized to give title compound as a light yellow solid (153 mg,55%). The structure and purity was confirmed by ¹H NMR and LCMS.

Example 36: Synthesis of Compound 394

Compound 394 (as shown in FIG. 1) was synthesized according to GeneralScheme 6, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 3:3-(4-(7-((trans)-4-hydroxycyclohexyl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-1-yl)-1-methylpyrrolidin-2-one

In a conical microwave vial were added3-(4-iodo-1H-pyrazol-1-yl)-1-methylpyrrolidin-2-one (30.4 mg, 105 μmol),(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(30.0 mg, 69.7 μmol) and cesium carbonate (57.7 mg, 174 μmol). Then DME(697 μL) and water (303 μL) were added and the resulting mixture was setto 3 cycles of vacuum and argon sparging. XPhos Palladacycle Gen. 4(3.06 mg, 3.49 μmol) was then added, the vial was sealed and thereaction mixture was irradiated in a microwave apparatus at 90° C. for10 minutes. After the reaction mixture was cooled to ambienttemperature, the crude mixture was concentrated to dryness. The crudemixture was purified on a 12 g silica column (dry pack) eluting with (A)DCM and (B) 20% McOH in DCM (gradient from 5% to 50%). The product wasdissolved in a mixture of ACN/water and was lyophilized affording thetitle product as a yellow powder (10 mg, 30%). The structure and puritywas confirmed by ¹H NMR and LCMS.

Example 37: Synthesis of Compound 300

Compound 300 (as shown in FIG. 1) was synthesized according to GeneralScheme 7, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 1:7-((trans)-4-aminocyclohexyl)-5-bromo-N—((S)-1-methoxypropan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

A solution of(cis)-4-(5-bromo-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-ol(259 mg, 677 μmol) and triphenylphosphine (215 mg, 812 μmol) in THF (3.0mL) was cooled to 0° C. and treated with N,N-diisopropylethylamine (150μL, 859 μmol) followed by diisopropyl azodicarboxylate (170 μL, 846μmol). After stirring for 45 min, the mixture was treated with diphenylphosphoryl azide (180 μL, 812 μmol) and allowed to warm to RT whilestirring overnight. The mixture was treated with triphenylphosphine (215mg, 812 μmol), and allowed to stir overnight. The mixture was thentreated with water (100 μL) and the mixture was allowed to stir at 50°C. overnight. The reaction was concentrated and the residue was purifiedby column chromatography (Combiflash, 25 g column, 0 to 30% McOH inDCM). The crude was used as is in the next step.

Step 2:7-((trans)-4-aminocyclohexyl)-N—((S)-1-methoxypropan-2-yl)-5-(4-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

A mixture of7-((trans)-4-aminocyclohexyl)-5-bromo-N—((S)-1-methoxypropan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(120 mg, 314 μmol), 4-(morpholinomethyl)phenyl-boronic acid (106 mg, 471μmol) and sodium hydrogenocarbonate (36.6 μL, 942 μmol) in and H2O (0.1mL) was degassed by bubbling nitrogen through the mixture for 5 min. Themixture was then treated with1,1-bis(diphenylphosphino)ferrocene-palladium dichloride (23.3 mg, 31.4μmol) and heated at 80° C. for 90 min. The reaction mixture was pouredinto water and extracted with EtOAc (×3). The combined organic layerswere washed (water, brine), dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by Reverse Phase chromatography (C18, 30 g)eluting with MeCN and water containing 10 mM AMF. The desired compoundwas obtained as a yellow solid (85 mg, 56%).

Step 3:N-((trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)acetamide

7-((trans)-4-aminocyclohexyl)-N—((S)-1-methoxypropan-2-yl)-5-(4-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(40.5 mg, 0.142 mmol), acetic acid (6 μL, 0.105 mmol) and DIPEA (62.1μL, 0.356 mmol) was dissolved in DMF (3.0 mL). Then, HATU (52.4 mg,0.134 mmol) was added to the reaction and it was left to stir overnightat RT. Upon completion, the mixture was then loaded directly onto a 60gram C18 column and the desired product was eluted using 0-100% MeCN in10 mM AmB. The organic solvent was removed in vacuo, then the aqueouswas lyophilized to give title compound as a yellow solid (16.0 mg, 36%).The structure and purity was confirmed by ¹H NMR and LCMS.

Example 38: Synthesis of Compound 316

Compound 316 (as shown in FIG. 1) was synthesized according to GeneralScheme 7, above. The step numbers indicated below correspond to thesteps shown in that scheme.

Step 3:3-(((trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(4-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)amino)-4-(methylamino)cyclobut-3-ene-1,2-dione(the starting material was prepared in example 36)

7-((trans)-4-aminocyclohexyl)-N—((S)-1-methoxypropan-2-yl)-5-(4-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(55.0 mg, 0.115 mmol) was dissolved in McOH (3.0 mL). Then,3,4-diethoxy-3-cyclobutene-1,2-dione (0.02 mL, 0.128 mmol) was added tothe mixture and the reaction was stirred overnight at RT until fullconsumption was observed. Then, a 2 M solution of methylamine in THF(1.28 mL, 2.57 mmol) was added the reaction was stirred until fullconversion to the desired product was observed. The mixture was thenconcentrated and dissolved in a minimum of DMSO and loaded onto a 60gram C18 column. The column was run 0-100% MeCN in 10 mM AmB buffer. Theproduct was concentrated and lyophilized to give the title compound as ayellow solid (21.4 mg, 28% yield). The structure and purity wasconfirmed by ¹H NMR and LCMS.

Example 39: Synthesis of Compound 479 (as Shown in FIG. 1)

Step 1:(trans)-4-(5-(2-fluoropyridin-4-yl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

In a 20 mL microwave vial were added(trans)-4-(5-(2-fluoropyridin-4-yl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(600 mg, 1.57 mmol), cesium carbonate (1.24 g, 3.76 mmol) and2-fluoropyridin-4-yl-boronic acid (331 mg, 2.35 mmol). DME (10 mL) andwater (4 mL) were then added and the resulting mixture was sparged withargon for 8 minutes in the sonication bath. Finally, XPhos PalladacycleGen. 4 (27.5 mg, 31.3 μmol) was added, the vial was sealed and thereaction mixture was irradiated in a microwave apparatus at 90° C. for25 min. The mixture was diluted with EtOAc concentrated to dryness. Thecrude product was purified on a 40 g silica column (dry pack) elutingwith (A) DCM and (B) 20% IPA in DCM (gradient from 5% to 60%). Theproduct was dissolved in a minimum of ACN and then water was added. Thecloudy solution was frozen and lyophilized, affording the title productas a yellow powder obtained (515 mg, 82%).

Step 2:(trans)-4-(2-(((S)-1-methoxypropan-2-yl)amino)-5-(2-(2-methyl-4H-pyrrolo[3,4-d]thiazol-5(6H)-yl)pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol

In a 2.5 mL sealed tube,(trans)-4-(5-(2-fluoropyridin-4-yl)-2-(((S)-1-methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol(60.0 mg, 150 μmol) was dissolved in DMSO (1.20 mL) and2-methyl-4H,5H,6H-pyrrolo[3,4-D][1,3]thiazole dihydrobromide (143 mg,451 μmol) was added followed by potassium carbonate (83 mg, 601 μmol).The reaction mixture was heated for 16 hours at 135° C. in an oil bath.Next morning, LCMS indicated limited conversion. The reaction was cooledto RT and cesium carbonate (198 mg, 601 μmol) was added. The reactionwas then heated again to 135° C. for 2 days. The reaction was thendiluted with EtOAc and water and the organic phase was washed with HCl1N, aqueous saturated NaHCO₃ and then brine. The organic phase was driedwith MgSO₄, filtered and concentrated under reduced pressure. Theproduct was purified on a 12 g silica column (dry pack) eluting with (A)DCM and (B) 20% IPA (gradient 10-90%). The residue was then purified on12 g C-18 column. Product eluted with (A) 10 μM AMF and (B) ACN(gradient 10-90%). The product was concentrated and lyophilized to givethe title compound as a yellow solid (19.0 mg, 24%). The structure andpurity was confirmed by ¹H NMR and LCMS.

Example 40: Synthesis of Compound 325 (as Shown in FIG. 1)

Step 1:(S)—N-(1-methoxypropan-2-yl)-5-(2-methylpyridin-4-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine

A mixture of(S)-5-bromo-N-(1-methoxypropan-2-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(379 mg, 891 μmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (421mg, 1.86 mmol) and sodium hydrogenocarbonate (247 mg, 2.94 mmol) indioxane (6.00 mL) and water (2.00 mL) was degassed by evacuating andbackfilling the flash with argon. The residue was treated with1,1-bis(diphenylphosphino)ferrocene-palladium dichloride (37.7 mg, 50.8μmol) and then heated at 80° C. for 4 hours. The reaction mixture waspoured into water and extracted with EtOAc (×3). The combined organiclayers were washed (water, brine), dried (Na₂SO₄) and concentrated invacuo. The residue was purified by column chromatography (Combiflash, 50g column, 10 to 100% IPA in DCM to give the title product as a yelloworange oil (336 mg/86%).

Step 2:(S)-4-(2-((1-methoxypropan-2-yl)amino)-5-(2-methylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone

A solution of(S)—N-(1-methoxypropan-2-yl)-5-(2-methylpyridin-4-yl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine(336 mg, 768 μmol) in ACN (10.0 mL) was treated with HCl (solution inwater, 2.00 mL, 12.0 mmol) and the reaction was allowed to stir for 4hours. The mixture was poured carefully into saturated NaHCO₃ andextracted with three times with EtOAc. The combined organic layers werewashed (water, brine) and dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by column chromatography (Combiflash, 50 g column,0 to 100% IPA in DCM) to give the title product (221 mg, 73%).

Step 3:(S)-8-(2-((1-methoxypropan-2-yl)amino)-5-(2-methylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,3-diazaspiro[4.5]decane-2,4-dione

A mixture of(S)-4-(2-((1-methoxypropan-2-yl)amino)-5-(2-methylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-one(120 mg, 305 μmol), ammonium carbonate (87.9 mg, 915 μmol) and potassiumcyanide (31.0 mg, 457 μmol) in McOH (5.00 mL) was allowed to stir at 65°C. overnight. Upon completion, water and EtOAc were added. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The product was purified on a 10 g silica column eluting with(A) DCM and (B) 20% IPA (dry pack). The product was dispersed in aminimum of ACN and then water was added. Cloudy slurry solution wasfrozen and lyophilized to give the title product as a yellow powder(41.0 mg, 29%, mixture of diastereoisomers). The structure and puritywas confirmed by ¹H NMR and LCMS.

The synthetic protocols and intermediates described above were used toprepare other compounds disclosed herein as indicated below. Thechemical structure, synthesis protocol, and NMR and LC-MS data obtainedfor exemplary compounds of the invention are shown in the table ofFIG. 1. One of ordinary skill in the art will be readily able to makeother compounds of the invention based on the general synthesis schemes,intermediate synthesis protocols, and specific compound synthesisprotocols set forth herein. In some embodiments, a provided compound isa compound depicted in FIG. 1 or a pharmaceutically acceptable saltthereof.

Example 41: Kinase Activity Assay

IC₅₀ values for compound inhibition of AXL, FLT3, MERTK and TYRO3activity were determined by using a TR-FRET activity assay. Apolypeptide substrate with a fluorescent label is phosphorylated on atyrosine by each enzyme, where the now phosphorylated product is boundby a Europium-labeled antibody specific to that phosphorylation site.The proximity between the antibody and the substrate gives a signalknown as TR-FRET. As the enzyme is inhibited by compound, lessphosphorylated peptide product is made causing a decrease in overallsignal.

Activity assays were performed in a 384-well, small volume, blackmicroplates in an active enzyme volume of 10 μL and final developedvolume of 20 μL. Final assay conditions are 50 mM HEPES pH 7.5, 10 mMMgCl₂, 1 mM EGTA, 0.01% Brij 35 and 1 mM DTT all at RT. Enzyme,substrate labeled peptide and compound are mixed, and then the reactionis initiated with the addition of ATP at Km concentration for eachenzyme. The reaction is allowed to run 60 minutes and then quenched witha 12.5 mM EDTA (ethylenediamine tetraacetic acid) solution. The plate isthen developed with the addition of Europium labeled antibody for afinal volume of 20 μL and is then incubated for 30 minutes in darkness.Plates are read in a Pherastar plate reader. Data is analyzed inGraphPad PRISM.

The results of these assays are shown in Table 1, below, wherein “No.”designates compound number (FIG. 1); “A” represents a value of <100 nM;“B” a value of >100 nM and <1 μM; “C” a value of >1 μM and <10 μM; “D” avalue of >10 μM; “ND” is not determined. The ratio of Mer to FLT3 iscalculated as follows: FLT3 IC₅₀/Mer IC₅₀. “+” represents a ratioof >2.0 and <10; “++” represents a ratio of between 10 and 100; and“+++” represents a ratio of >100.

TABLE 1 Activity of Exemplary Compounds against Various Kinases andRatio of Mer Activity to FLT3 Activity. No. Axl Flt3 Mer Tyro3 FLT3/Mer101 A A A ND + 102 B B A A ++ 103 B B A B ++ 104 A B A A ++ 105 B B AA + 106 D D B ND ++ 107 A B A A +++ 108 B B A B +++ 109 A B A A ++ 110 AB A A ++ 111 D C C ND + 112 B B A A +++ 113 A B A A ++ 114 A B A A +++115 B C A B ++ 116 A B A A +++ 117 B C A B +++ 118 A A A A ++ 119 B C AA +++ 120 B C A A +++ 121 B B A A ++ 122 A B A A +++ 123 C C A B +++ 124A B A A ++ 125 B C A B ++ 126 B C A B ++ 127 A B A A +++ 128 A A A A ++129 B C A A +++ 130 A A A A +++ 131 A A A A +++ 132 A A A A ++ 133 A B AA +++ 134 A C A A +++ 135 A B A A +++ 136 B C A B +++ 137 A B A A +++138 B B A A ++ 139 A C A A +++ 140 A B A A +++ 141 A B A A +++ 142 A B AA +++ 143 A A A A ++ 144 A B A A +++ 145 A A A A ++ 146 B C A A +++ 147B C A A +++ 148 A B A A +++ 149 B B A A ++ 150 A B A A ++ 150-1 ND ND NDND ND 151 B B A A +++ 152 A B A A +++ 153 B C A A +++ 154 A B A A +++155 A B A A ++ 156 A B A A ++ 157 A A A A ++ 158 A B A A +++ 159 A B A A+++ 160 A C A A +++ 161 B A A A ++ 162 A B A A +++ 163 A B A A ++ 164 AA A A ++ 165 A A A A ++ 166 A A A A ++ 167 A B A A +++ 168 C C A B +++169 A C A A +++ 170 A C A A +++ 171 A A A A ++ 172 A A A A ++ 173 A B AA +++ 174 B C A A +++ 175 C C B C ++ 176 C C C C + 177 C C A B +++ 178 CC A B +++ 179 B B A A +++ 180 B B A A ++ 181 B A A A ++ 182 A A A A ++183 B C A A +++ 184 B B A A ++ 185 A B A A ++ 186 B B A A ++ 187 A B A A+++ 188 A A A A +++ 189 A A A A ++ 190 A A A A +++ 191 B C A A +++ 192 CC B C ++ 193 A C A A +++ 194 B C A A +++ 195 B C A A +++ 196 A B A A +++197 A B A A +++ 198 B B A A +++ 199 A B A A +++ 200 B C A A +++ 201 B CA A +++ 202 B B A A +++ 203 A A A A ++ 204 C C B B ++ 205 C C A A +++206 B C A A +++ 207 A B A A +++ 208 B C A A +++ 209 B B A A +++ 210 B CA A +++ 211 B B A A ++ 212 B C A B ++ 213 A A A A +++ 214 B C A A +++215 B C A A +++ 216 A A A A ++ 217 B B A A +++ 218 B B A A +++ 219 B C AA +++ 220 A B A A +++ 221 A B A A +++ 222 A B A A +++ 223 B C A A +++224 B B A A +++ 225 A B A A +++ 226 B B A A +++ 227 B C A A +++ 228 B CA A +++ 229 A B A A +++ 230 B B A A +++ 231 B C A A +++ 232 B C A A +++233 B C A A +++ 234 B C A A +++ 235 B C A A +++ 236 ND ND ND ND ND 237 BB A A +++ 238 B B A A +++ 239 A B A A +++ 240 B B A A +++ 241 B B A A+++ 242 A B A A +++ 243 A B A A +++ 244 A A A A ++ 245 B C A A +++ 246 AB A A +++ 247 B C A A +++ 248 B C A A +++ 249 A B A A +++ 250 B C A A+++ 251 B B A A +++ 252 B B A A +++ 253 C C A A +++ 254 B B A A +++ 255A A A A ++ 256 A B A A +++ 257 C C A B +++ 258 B C A A ++ 259 A B A A+++ 260 B B A A +++ 261 B C A A +++ 262 A A A A +++ 263 A A A A ++ 264 AC A A +++ 265 A C A A +++ 266 A B A A +++ 267 B C A A +++ 268 B B A A+++ 269 A A A A ++ 270 A A A A +++ 271 A A A A ++ 272 B B A A +++ 273 AB A A +++ 274 A A A A +++ 275 A C A A +++ 276 A B A A +++ 277 A A A A+++ 278 A B A A +++ 279 A B A A +++ 280 A B A A +++ 281 A A A A +++ 282A B A A +++ 283 A C A A +++ 284 B C A A +++ 285 A B A A +++ 286 A A A A+++ 287 A A A A +++ 288 A A A A ++ 289 A A A A + 290 A A A A ++ 291 A BA A +++ 292 A B A A +++ 293 A B A A +++ 294 A A A A +++ 295 A C A A +++296 A A A A ++ 297 A A A A ++ 298 A C A A +++ 299 A C A A +++ 300 A B AA +++ 301 A A A A +++ 302 A B A A +++ 303 A B A A +++ 304 A C A A +++305 A B A A +++ 306 A B A A +++ 307 A A A A +++ 308 B C A A +++ 309 A BA A +++ 310 A B A A +++ 311 A B A A +++ 312 A A A A +++ 313 A B A A +++314 A A A A +++ 315 A B A A +++ 316 A A A A ++ 317 A A A A +++ 318 A C AA +++ 319 A C A A +++ 320 A C A A +++ 321 A A A A +++ 322 A B A A +++323 A B A A +++ 324 A B A A +++ 325 A C A A +++ 326 A C A A +++ 327 A CA A +++ 328 A C A A +++ 329 A B A A +++ 330 A B A A +++ 331 A B A A +++332 A B A A +++ 333 A B A A +++ 334 B C A A +++ 335 B C A A +++ 336 A BA A +++ 337 A B A A +++ 338 A B A A +++ 339 A B A A +++ 340 A B A A +++341 A B A A +++ 342 A B A A +++ 343 A C A A +++ 344 A B A A +++ 345 A CA A +++ 346 A A A A +++ 347 A A A A +++ 348 A B A A +++ 349 C C A A +++350 A A A A +++ 351 A A A A ++ 352 A A A A ++ 353 B B A A +++ 354 A B AA +++ 355 A A A A + 356 A A A A ++ 357 A B A A +++ 358 A C A A +++ 359 AA A A + 360 A A A A ++ 361 A C A A +++ 362 A A A A ++ 363 A A A A + 364A A A A +++ 365 A B A A +++ 366 A C A A +++ 367 A C A A +++ 368 A B A A+++ 369 A B A A +++ 370 A A A A + 371 C C A B +++ 372 C C B C ++ 373 B CA A +++ 374 A C A A +++ 375 B C A A +++ 376 B C A A +++ 377 B C A A +++378 C C A B +++ 379 A B A A +++ 380 A B A A +++ 381 A C A A +++ 382 A BA A +++ 383 B C A A +++ 384 A A A A +++ 385 B C A A +++ 386 A B A A +++387 C C B B ++ 388 C C B C ++ 389 A B A A +++ 390 A B A A +++ 391 A B AA +++ 392 A A A A +++ 393 A A A A +++ 394 A B A A +++ 395 A B A A +++396 A B A A +++ 397 A B A A +++ 398 A C A A +++ 399 A B A A +++ 400 A BA A +++ 401 A B A A +++ 402 A B A A +++ 403 A B A A +++ 404 A B A A +++405 A A A A +++ 406 B B A A +++ 407 A B A A +++ 408 A B A A +++ 409 C DA C +++ 410 B C A A +++ 411 A B A A +++ 412 A A A A +++ 413 A A A A ++414 A C A A +++ 415 A C A A +++ 416 A B A A +++ 417 B D A A +++ 418 A BA A +++ 419 A B A A +++ 420 A B A A +++ 421 A B A A +++ 422 A B A A +++423 A B A A +++ 424 A B A A +++ 425 A B A A +++ 426 A B A A +++ 427 A BA A +++ 428 C C B A ++ 429 B A A A ++ 430 A B A A +++ 431 A B A A +++432 A B A A +++ 433 B C A A +++ 434 A B A A +++ 435 C C A B +++ 436 A BA A +++ 437 A A A A +++ 438 A C A A +++ 439 A B A A +++ 440 A C A A +++441 A A A A ++ 442 A A A A ++ 443 A C A A +++ 444 A B A A +++ 445 A B AA +++ 446 A A A A +++ 447 C C C C + 448 A C A A +++ 449 B C A A +++ 450A C A A +++ 451 A B A A +++ 452 A B A A +++ 453 A B A A +++ 454 A A A A++ 455 A A A A ++ 456 A A A A +++ 457 A B A A +++ 458 A A A A +++ 459 AC A A +++ 460 A A A A +++ 461 A C A A +++ 462 A B A A +++ 463 A B A A+++ 464 A B A A +++ 465 A C A A +++ 466 A C A A +++ 467 A C A A +++ 468A B A A +++ 469 A B A A +++ 470 A B A A +++ 471 A C A A +++ 472 A B A A+++ 473 A B A A +++ 474 A B A A +++ 475 A B A A +++ 476 A B A A +++ 477A C A A +++ 478 A C A A +++ 479 A C A A +++ 480 A B A A +++ 481 C C A B+++ 482 A A A A +++ 483 A B A A +++ 484 B C A A +++ 485 A B A A +++ 486A C A A +++ 487 B C A A +++ 488 A B A A +++ 489 A A A A +++ 490 A B A A+++ 491 A B A A +++ 492 A C A A +++ 493 A B A A +++ 494 A C A A +++ 495A C A A +++ 496 A C A A +++ 497 B C A A +++ 498 A B A A +++ 499 A B A A+++ 500 A B A A +++ 501 B C A A ++ 502 B C A A ++ 503 B C A A +++ 504 AB A A +++ 505 A C A A +++ 506 C D A A +++ 507 A B A A +++ 508 A C A A+++ 509 A C A A +++ 510 B C A A +++ 511 C B A A ++ 512 A B A A +++ 513 AB A A +++ 514 A C A A +++ 515 B B A A +++ 516 A C A A +++ 517 A C A A+++ 518 A C A A +++ 519 A C A A +++ 520 B C A A +++ 521 B B A A ++ 522 BB A A +++ 523 A B A A +++ 524 A B A A +++ 525 B C A A +++ 526 C C A A ++527 B B A A +++ 528 A B A A +++ 529 B C A A +++ 530 B B A A ++ 531 B B AA +++ 532 A C A A +++ 533 A C A A +++ 534 A B A A +++ 535 A A A A ++ 536B C A A +++ 537 A C A A +++ 538 B C A A +++ 539 B C A A +++ 540 A A A A+++ 541 A A A A ++ 542 C C A A +++ 543 C C A A +++ 544 C C B A ++ 545 CB A A + 546 A B A A +++ 547 A B A A +++ 548 A B A A +++ 549 A B A A +++550 A B A A +++ 551 A C A A +++ 552 A B A A +++ 553 A B A A +++ 554 A CA A +++ 555 A C A A +++ 556 A C A A +++ 557 A B A A +++ 558 A B A A +++559 A B A A +++ 560 A B A A +++ 561 A B A A +++ 562 A A A A +++ 563 A BA A +++ 564 A A A A ++ 565 A B A A +++ 566 A B A A +++ 567 A C A A +++568 A B A A +++ 569 A B A A +++ 570 B B A A ++ 571 B B A A ++ 572 B D AA +++ 573 B D A A +++ 574 B C A A +++ 575 B C A A +++ 576 B C A A +++577 A C A A +++ 578 B C A A +++ 579 B C A A +++ 580 A A A A +++ 581 A AA A +++ 582 A C A A +++ 583 A B A A +++ 584 A C A A +++ 585 A C A A +++586 A C A A +++ 587 A B A A +++ 588 B B A A ++ 589 A B A A +++ 590 C C AB +++ 591 A C A A +++ 592 C C A A +++ 593 A B A A +++ 594 A C A A +++595 B C A A +++ 596 A B A A +++ 597 A B A A +++ 598 A B A A +++ 599 A CA A +++ 600 A C A A +++ 601 A C A A +++ 602 A C A A +++ 603 A C A A +++604 A C A A +++ 605 A B A A +++ 606 A C A A +++ 607 A C A A +++ 608 A AA A ++ 609 A A A A ++ 610 A A A A ++ 611 A B A A +++ 612 A B A A +++ 613A A A A +++ 614 A B A A +++ 615 A B A A +++ 616 A B A A +++ 617 A B A A+++ 618 A B A A +++ 619 A B A A +++ 620 A C A A +++ 621 A B A A +++ 622A C A A +++ 623 A C A A +++ 624 A A A A ++ 625 A B A A +++ 626 A A A A++ 627 A C A A +++ 628 A C A A +++ 629 A B A A +++ 630 A B A A +++ 631 AC A A +++ 632 A B A A +++ 633 A B A A +++

Example 42: Exemplary Compound in Combination with an Anti-PD1 AntibodyDemonstrates Synergy in Reducing Syngeneic Tumor

BLAB/c syngeneic mice challenged with colon carcinoma CT-26 cells wereused to test the tumor growth inhibitory activity of Compound 124 and ananti-PD1 antibody alone or in combination. CT-26 tumor cells weremaintained in vitro as a monolayer culture in RPMI-1640 mediumsupplemented with 10% heat inactivated fetal bovine serum, 100 U/mlpenicillin and 100 μg/ml streptomycin at 37° C. in an atmosphere of 5%CO₂ in air. The tumor cells were routinely subcultured twice weekly bytrypsin-EDTA treatment. The cells growing in an exponential growth phasewere harvested and counted for tumor inoculation. Balb/c female mice(6-8 weeks old; 18-22 g) were inoculated subcutaneously at the rightlower flank with CT-26 tumor cells (3×10⁵) in 0.1 ml of PBS for tumordevelopment. Treatments were started on day 8 after tumor inoculationwhen the average tumor size reached approximately 56 mm³.

Mice (8 for each regimen) were dosed with one of the following regimens:(1) twice daily oral dosing with 100 mg/kg of Compound 124; (2) biweeklyIP injections with 10 mg/kg of anti-PD1 antibody (clone RMP1-14); (3) acombination of twice daily Compound 124 (100 mg/kg) and biweeklyanti-PD1 antibody (10 mg/kg) or (4) an orally dosed vehicle control.Subcutaneous tumor volumes were measured three times per week startingat three days post-first dosing using caliper measurements in 2dimensions (looking down at the tumor, using the calipers to make 2diameter measurements at right angles to each other). The tumor volumewas then calculated using the following standard formula: TumorVolume=0.5*A*B², wherein A=longest diameter of the tumor; and B=shortestdiameter of the tumor. As shown in FIG. 3, mice treated with acombination of Compound 124 and anti-PD1 demonstrated slower tumorgrowth than mice treated with either agent as a monotherapy.

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims are introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists every possible subgroup of the elements is alsodisclosed, and any element(s) can be removed from the group. It shouldit be understood that, in general, where the invention, or aspects ofthe invention, is/are referred to as comprising particular elementsand/or features, certain embodiments of the invention or aspects of theinvention consist, or consist essentially of, such elements and/orfeatures. For purposes of simplicity, those embodiments have not beenspecifically set forth in haec verba herein. Where ranges are given,endpoints are included. Furthermore, unless otherwise indicated orotherwise evident from the context and understanding of one of ordinaryskill in the art, values that are expressed as ranges can assume anyspecific value or sub-range within the stated ranges in differentembodiments of the invention, to the tenth of the unit of the lowerlimit of the range, unless the context clearly dictates otherwise.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the disclosure described and claimed herein. Suchequivalents are intended to be encompassed by the following claims.

1.-30. (canceled)
 31. A method of treating a patient who has cancer, themethod comprising administering to the patient a therapeuticallyeffective amount of a pharmaceutical composition, wherein the cancer isresistant to treatment with a checkpoint inhibitor; cells of the canceroverexpress one or more TAM kinases; the cancer is associated withelevated myeloid infiltration relative to a comparable biological sampleor reference standard; and/or the cancer is a breast cancer, ovariancancer, glioblastoma, pancreatic ductal adenocarcinoma, non-small celllung cancer, colorectal cancer, leukemia, lymphoma, gastric cancer,prostate cancer, pituitary adenoma, melanoma, or rhabdomyosarcoma andthe pharmaceutical composition comprises a pharmaceutically acceptablecarrier and a compound of structural formula II

or a pharmaceutically acceptable salt thereof, where: R¹ ispyridin-3-yl, pyridin-4-yl, pyrazol-4-yl, cyclohexyl, or8-azabicyclo[3.2.1]oct-2-ene-3-yl, wherein R¹ is optionally substitutedwith up to four independently selected substituents; R² is cyclohexylsubstituted with hydroxy and optionally substituted with one or twoadditional substituents independently selected from C₁-C₄ alkyl andfluoro, or is 4,5,6,7-tetrahydro-1H-indazolyl optionally substitutedwith one to three substituents independently selected from C₁-C₄ alkyland fluoro; and R³ is —C₃-C₈ alkyl, —(C₂-C₆ alkylene)-O—(C₁-C₆ alkyl),C₃-C₆ cycloalkyl, or —(C₂-C₆ alkylene)-C₃-C₆ cycloalkyl, wherein R³ isoptionally substituted with 1-5 substituents independently selected fromdeuterium, halo, and —OH.
 32. The method of claim 31, wherein, in thecompound or the pharmaceutically acceptable salt thereof, R¹ isoptionally substituted with up to four substituents independentlyselected from halo, hydroxy, —CN, —(C₁-C₄ alkyl optionally substitutedwith one or more substituents selected from cyano, hydroxy and halo),—C(O)NH₂, —COOH, —(C₀-C₃ alkylene)-C(O)—(C₁-C₄ alkyl), —(C₀-C₃alkylene)-C(O)—NH—(C₁-C₄ alkyl), —(C₀-C₃ alkylene)-C(O)—NH—S(O)₂—(C₁-C₄alkyl), —(C₀-C₃ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₃ alkylene)-COOH,—(C₀-C₄ alkylene)-S(O)₂—(C₁-C₃ alkyl), —(C₁-C₃ alkylene)-O—(C₁-C₄alkyl), —S(O)(═NH)—(C₁-C₄ alkyl), S(O)₂—NH—(C₁-C₄ alkyl),-(cyclopropyl)-(cyano-substituted C₁-C₃ alkyl),-(cyclopropyl)-C(O)—NH—(C₁-C₄ alkyl), —(C₀-C₃alkylene)-C(O)-heterocyclyl, —C(O)—(C₀-C₃ alkylene)-heterocyclyl,-(cyclopropyl)-C(O)-heterocyclyl, —(C₀-C₄ alkylene)-heterocyclyl,—(C₀-C₃ alkylene)-C(O)—NH— heterocyclyl, —(C₀-C₄ alkylene)-aryl, and—(C₀-C₄ alkylene)-heteroaryl, wherein the heterocyclyl or heteroarylportion of the R¹ substituent is optionally further substituted.
 33. Themethod of claim 31, wherein, in the compound or the pharmaceuticallyacceptable salt thereof, R¹ is1-((1-oxetan-3-ylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(1-trifluoromethylcyclopropylcarbonyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2,2-trifluoroethan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(2,2-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2,6-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(3,3,3-trifluoropropan-1-yl)azetidin-3-yl)pyrazol-4-yl,1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(azetidin-1-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(ethan-2-ylsulfonyl)-3-(cyanomethyl)azetidin-3-yl)pyrazol-4-yl,1-(1-(hexahydro-1H-furo[3,4-c]pyrrol-5-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(isopropylaminocarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl,1-(1-(morpholin-4-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1-(pyrrolidin-1-ylcarbonyl)cyclopropyl)pyrazol-4-yl,1-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazol-4-yl,1-(1,3-dimethylpyrazol-5-yl)pyrazol-4-yl,1-(1-acetylazetidin-3-yl)pyrazol-4-yl,1-(1-acetylpyrrolidin-3-yl)pyrazol-4-yl,1-(1-cyanocyclopropylmethyl)pyrazol-4-yl,1-(1H-pyrazol-4-ylmethyl)pyrazol-4-yl,1-(1-hydroxy-3-chloropropan-2-yl)pyrazol-4-yl,1-(1-hydroxylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methoxycarbonylazetidin-3-yl)pyrazol-4-yl,1-(1-methyl-2(1H)-pyridinon-5-ylmethyl)pyrazol-4-yl,1-(1-methyl-2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(1-methylaminocarbonyl-1-methylethan-1-yl)pyrazol-4-yl,1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl,1-(1-t-butoxycarbonylpyrrolidin-3-yl)pyrazol-4-yl,1-(2-(1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-1,3,4-oxadiazol-5-yl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3,5-dimethylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylazetidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxy-3-methylpyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(3-hydroxypyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-cyano-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4yl,1-(2-(4-hydroxy-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(4-methylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(morpholin-4-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-difluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl,1-(2-(methyl)-2-(morpholin-4-yl)propan-3-yl)pyrazol-4-yl,1-(2-(methyl)-3-(morpholin-4-yl)propan-2-yl)pyrazol-4-yl,1-(2-(pyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl,1-(2-cyanoethyl)pyrazol-4-yl,1-(2-hydroxy-2-methylpropan-1-yl)pyrazol-4-yl,1-(2-methoxyethyl)pyrazol-4-yl,1-(2-methyl-3-hydroxypropan-2-yl)pyrazol-4-yl,1-(2-methylpropyl)pyrazol-4-yl,1-(2-methylsulfonylethan-1-yl)pyrazol-4-yl,1-(2-morpholin-4-ylethyl)pyrazol-4-yl,1-(2-oxopyrrolidin-3-yl)pyrazol-4-yl,1-(2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl,1-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)pyrazol-4-yl,1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(4-methylpiperazin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl,1-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)pyrazol-4-yl,1-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)pyrazol-4-yl,1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(5-oxopyrrolidin-2-ylmethyl)pyrazol-4-yl,1-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)pyrazol-4-yl,1-(6-methylpyrazin-2-ylmethyl)pyrazol-4-yl,1-(ethoxycarbonylmethyl)pyrazol-4-yl,1-(hexahydrofuro[2,3-b]furan-3-yl)pyrazol-4-yl,1-(hydroxycarbonylmethyl)pyrazol-4-yl,1-(isopropylaminocarbonylmethyl)pyrazol-4-yl,1-(isopropylcarbonylmethyl)pyrazol-4-yl,1-(methylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylaminocarbonylmethyl)pyrazol-4-yl,1-(methylsulfonylmethyl)pyrazol-4-yl,1-(morpholin-4-ylcarbonylmethyl)pyrazol-4-yl,1-(oxetan-2-ylmethyl)pyrazol-4-yl, 1-(oxetan-3-ylmethyl)pyrazol-4-yl,1-(pyrazin-2-ylmethyl)pyrazol-4-yl,1-(pyridazin-4-ylmethyl)pyrazol-4-yl,1-(pyridin-3-ylmethyl)pyrazol-4-yl,1-(pyrrolidin-1-ylcarbonylmethyl)pyrazol-4-yl,1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl,1-(tetrahydrofuran-3-yl)pyrazol-4-yl,1-(tetrahydrofuran-3-ylaminocarbonylmethyl)pyrazol-4-yl,1-(tetrahydropyran-4-yl)pyrazol-4-yl,1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl, 1,3-dimethylpyrazol-4-yl,1-difluoromethylpyrazol-4-yl, 1H-pyrazol-4-yl, 1-methylpyrazol-3-yl,1-methylpyrazol-4-yl, 1-oxetan-3-ylpyrazol-4-yl, 1-t-butylpyrazol-4-yl,2-(1,1-dioxothiomorpholin-4-yl)pyridin-4-yl,2-(1-methylpiperidin-3-yloxy)pyridin-4-yl,2-(1-methylpiperidin-4-yloxy)pyridin-4-yl,2-(1-methylpyrrolidin-3-yloxy)pyridin-4-yl,2-(2-methoxyethan-1-yloxy)pyridin-4-yl,2-(3-oxopiperazin-1-yl)pyridin-4-yl,2-(4-acetylpiperazin-1-yl)pyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl,2-(4-methylsulfonylpiperazin-1-yl)pyridin-4-yl,2-(morpholin-4-yl)pyridin-4-yl, 2-(oxetan-3-yloxy)pyridin-4-yl,2-(piperidin-3-yloxy)pyridin-4-yl, 2-(piperidin-4-yloxy)pyridin-4-yl,2-(pyrrolidin-3-yloxy)pyridin-4-yl, 2,6-dimethylpyridin-4-yl,2-isopropoxypyridin-4-yl, 2-isopropylaminopyridin-4-yl,2-methylaminocarbonyl-6-methylpyridin-4-yl,2-methylaminocarbonylpyridin-4-yl, 2-methylaminopyridin-4-yl,2-methylpyridin-4-yl, 2-morpholin-4-ylpyridin-4-yl,2-pyrrolidin-1-ylpyridin-4-yl,4-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclohexyl,4-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)cyclohexyl,4-(4,4-difluoropiperidin-1-ylcarbonyl)cyclohexyl,4-(4-methylpiperazin-1-yl)carbonylcyclohexyl,4-(morpholin-4-ylcarbonyl)cyclohexyl, 4-hydroxycarbonylcyclohexyl,4-methylpyridin-3-yl, 5-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,5-(morpholin-4-ylmethyl)pyridin-3-yl,5-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl,5-(S-imino(methyl)sulfinyl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl,5-cyanopyridin-3-yl, 5-dimethylaminocarbonylpyridin-3-yl,5-fluoropyridin-3-yl, 5-hydroxycarbonylpyridin-3-yl,5-methylaminocarbonylpyridin-3-yl, 5-methylaminosulfonylpyridin-3-yl,5-methylpyridin-3-yl, 5-methylsulfonylpyridin-3-yl,6-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-yl)pyridin-4-yl,6-(1-methylpiperazin-4-yl)pyridin-3-yl,6-(2-(2-hydroxypropan-2yl)morpholin-4-yl)pyridin-4-yl,6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-4-yl,6-(2-hydroxypropan-2-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-5-yl)pyridin-4-yl,6-(2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-5-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl,6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-4-yl,6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(2-oxo-oxazol-3-yl)pyridin-4-yl,6-(3-methyl-3-hydroxyazetidin-1-yl)pyridin-4-yl,6-(3-methyl-3-hydroxypyrrolidin-1-yl)pyridin-4-yl,6-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl,6-(3-oxomorpholin-4-yl)pyridin-4-yl,6-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(N-isopropyl-N-ethylaminocarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylcarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-4-yl,6-(4-(oxetan-3-yloxycarbonyl)piperazin-1-yl)pyridin-4-yl,6-(4-methoxycarbonylpiperazin-1-yl)pyridin-4-yl,6-(4-methyl-4-hydroxypiperidin-1-yl)pyridin-4-yl,6-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl,6-(4-methylpiperazin-1-ylmethyl)pyridin-4-yl,6-(4-trifluoromethylsulfonylpiperazin-1-yl)pyridin-4-yl,6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl,6-(hexahydro-1H-furo[3,4-c]pyrrol-5-yl)pyridin-4-yl,6-(isopropylaminocarbo-nyl)pyridin-3-yl,6-(methylaminocarbonyl)pyridin-3-yl, 6-(morpholin-4-yl)pyridin-4-yl,6-(morpholin-4-ylcarbonyl)pyridin-3-yl,6-(morpholin-4-ylmethyl)pyridin-3-yl, 6-(oxetan-3-yl)pyridin-4-yl,6-(piperazin-1-yl)pyridin-4-yl, 6-(pyridin-3-yloxy)pyridin-4-yl,6-(S-imino(methyl)sulfinyl)pyridin-4-yl,6-(S-methyl-S-iminosulfinyl)pyridin-3-yl,6-(tetrahydro-pyran-3-ylamino)pyridin-4-yl,6-(tetrahydropyran-4-ylamino)pyridin-4-yl, 6-fluoropyridin-4-yl,6-methylaminosulfonylpyridin-3-yl, 6-methylpyridin-3-yl,6-methylpyridin-4-yl, or 6-methylsulfonylpyridin-3-yl.
 34. The method ofclaim 31, wherein, in the compound or the pharmaceutically acceptablesalt thereof, R² is 4-hydroxycyclohexyl optionally substituted with oneto three substituents selected from —CH₃ and fluoro, or is4,5,6,7-tetrahydro-1H-indazol-5-yl.
 35. The method of claim 31, wherein,in the compound or the pharmaceutically acceptable salt thereof, R³ isisopropyl, n-butanyl, heptan-2-yl, propan-2-yl, 3-methoxypropan-2-yl,3,3-(difluoromethoxy)propan-2-yl, 3,3-difluoropropan-2-yl,3-cyclopropylpropan-2-yl, 4,4,4-trifluorobutan-2-yl, 4-fluorobutan-2-yl,4,4-difluorobutan-2-yl, 2-methoxyethan-1-yl, 2-cyclopropanylethan-1-yl,or 3,3,3-trifluoropropan-1-yl.
 36. The method of claim 31, wherein, thecompound has structural Formula IV

or structural Formula V

or is a pharmaceutically acceptable salt thereof, wherein: R⁸ is —(C₀-C₄alkylene)-S(O)₂—(C₁-C₃ alkyl), —C(O)—NH—(C₁-C₄ alkyl), —C₁-C₄ alkyloptionally substituted with one or more of halo, hydroxy and cyano,—NH—(C₁-C₄ alkyl), —O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl), —O—(C₁-C₄alkyl), —S(O)(═NH)—(C₁-C₄ alkyl), —S(O)₂—NH—(C₁-C₄ alkyl), —(C₀-C₃alkylene)-C(O)-heterocyclyl, —(C₀-C₃ alkylene)-NH-heterocyclyl, —(C₀-C₄alkylene)-heterocyclyl, —O-heteroaryl, or —O-heterocyclyl, wherein anyheterocyclyl, or heteroaryl portion of R⁸ is optionally furthersubstituted; R⁷ is —O—C₁-C₃ alkyl, C₁-C₃ haloalkyl, or —O—C₁-C₃haloalkyl; R¹² is hydrogen or C₁-C₄ alkyl; and each of R^(13a) andR^(13b) is independently selected from hydrogen and fluoro.
 37. Themethod of claim 36, wherein, in the compound or the pharmaceuticallyacceptable salt thereof, R⁸ is —CH₃, —C(O)NHCH₃, —C(O)NHCH(CH₃)₂,—NHCH(CH₃)₂, —NHCH₃, —S(═O)(═NH)—CH₃, —S(═O)₂—CH₃, —S(═O)₂—NH—CH₃,1,1-dioxothiomorpholin-4-yl,1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl,1-methylpiperidin-3-yloxy, 1-methylpiperidin-4-yloxy,1-methylpyrrolidin-3-yloxy, 1-oxa-7-azospiro[3.5]nonan-7-yl,2-(2-hydroxypropan-2-yl)morpholin-4-yl,2,5-dioxa-8-azospiro[3.5]nonan-8-yl, 2-methoxyethan-1-yloxy,2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl,2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl,2-oxa-6-azospiro[3.3]heptan-6-yl, 2-oxa-6-azospiro[3.5]octan-6-yl,2-oxa-7-azospiro[3.5]nonan-7-yl, 2-oxo-oxazolidin-3-yl,3-oxomorpholin-4-yl, 3-oxopiperazin-1-yl,4-(N-ethyl-N-isopropylaminocarbonyl)piperazin-1-yl,4-(oxetan-3-yl)piperazin-1-yl, 4-(oxetan-3-ylmethyl)piperazin-1-yl,4-acetylpiperazin-1-yl, 4-cyclopropylsulfonylpiperazin-1-yl,4-methoxycarbonylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-sulfonylmethylpiperazin-1-yl,4-trifluoromethylsulfonylpiperazin-1-yl,8-oxa-3-azabicyclo[3.2.1]octan-3-yl, isopropyloxy, morpholin-4-carbonyl,morpholin-4-yl, morpholin-4-ylmethyl, oxetan-3-yl, oxetan-3-yloxy,piperazin-1-yl, piperidin-3-yloxy, piperidin-4-yloxy, pyridin-3-yloxy,pyrrolidin-1-yl, pyrrolidin-3-yloxy,tetrahydro-1H-furo[3,4-c]pyrrol-5-yl, tetrahydrofuran-3-ylamino, ortetrahydropyran-4-yl.
 38. The method of claim 36, wherein, in thecompound or the pharmaceutically acceptable salt thereof, R⁸ ismorpholin-4-yl, —S(═O)(═NH)—CH₃, or —S(═O)₂—CH₃.
 39. The method of claim36, wherein, in the compound or the pharmaceutically acceptable saltthereof, R⁷ is —OCH₃, —CF₃, or —OCHF₂.
 40. The method of claim 36,wherein, in the compound or the pharmaceutically acceptable saltthereof, R¹² is hydrogen or —CH₃.
 41. The method of claim 40, wherein,in the compound or the pharmaceutically acceptable salt thereof, each ofR¹², R^(13a) and R^(13b) is hydrogen and the compound has structuralformula IVa

or structural formula Va


42. The method of claim 31, wherein the compound has structural FormulaVI

or is a pharmaceutically acceptable salt thereof, wherein: R⁷ is—O—C₁-C₃ alkyl, C₁-C₃ haloalkyl, or —O—C₁-C₃ haloalkyl; each of R^(9a)and R^(9b) are —CH₃, or R^(9a) and R^(9b) are taken together with thecarbon atom to which they are bound to form cyclopropyl; R⁹ is C₁-C₃alkyl, C₁-C₃ hydroxyalkyl, —COOH, —C(O)NH—C₁-C₄ alkyl,—CH₂-heterocyclyl, —C(═O)-heterocyclyl or a 5-membered heteroaryl,wherein the heterocyclyl or heteroaryl portion of R⁹ is optionallysubstituted with up to two substituents independently selected from oxo,cyclopropyl, —OH, —CN, —C₁-C₃ alkyl, and —C₁-C₃ hydroxyalkyl; and R¹² ishydrogen or C₁-C₄ alkyl; and each of R^(13a) and R^(13b) isindependently selected from hydrogen and fluoro.
 43. The method of claim42, wherein, in the compound or the pharmaceutically acceptable saltthereof, R⁷ is —OCH₃, —CF₃, or —OCHF₂.
 44. The method of claim 42,wherein, in the compound or the pharmaceutically acceptable saltthereof, R⁹ is —CH₃, —CH₂OH, —COOH, —C(O)NHCH₃, —C(O)NHCH(CH₃)₂,1,1-dioxothiomorpholin-4-ylcarbonyl,2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl,2,2-dimethylmorpholin-4-ylcarbonyl,2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl,2,6-dimethylmorpholin-4-ylcarbonyl,2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl, 2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl, 3-hydroxpyrrolidin-1-ylcarbonyl,4-cyano-4-methylpiperidin-1-ylcarbonyl,4-hydroxy-4-methylpiperidin-1-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-oxadiazol-2-yl,8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl, azetidin-1-ylcarbonyl,morpholin-4-ylcarbonyl, morpholin-4-ylmethyl, pyrrolidin-1-ylcarbonyl,or tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylcarbonyl.
 45. The method ofclaim 44, wherein, in the compound or the pharmaceutically acceptablesalt thereof, R⁹ is morpholin-4-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, 2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl, 3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl. 46.The method of claim 42, wherein, in the compound or the pharmaceuticallyacceptable salt thereof, R¹² is hydrogen or —CH₃.
 47. The method ofclaim 46, wherein, in the compound or the pharmaceutically acceptablesalt thereof, each of R¹², R^(13a) and R^(13b) is hydrogen and thecompound has structural formula VIa


48. The method of claim 31, wherein the compound has structural FormulaVII

or is a pharmaceutically acceptable salt thereof, wherein: R^(7a) isC₁-C₄ alkyl, —O—C₁-C₃ alkyl, C₁-C₃ haloalkyl, or —O—C₁-C₃ haloalkyl; R⁹is —COOH, —C(═O)-heterocyclyl or a 5-membered heteroaryl, wherein R⁹ isoptionally substituted with up to two substituents independentlyselected from oxo, —OH and —C₁-C₃ alkyl; and R¹² is hydrogen, or C₁-C₄alkyl; and each of R^(13a) and R^(13b) is independently selected fromhydrogen and fluoro.
 49. The method of claim 48, wherein, in thecompound or the pharmaceutically acceptable salt thereof, R^(7a) is—(CH₂)₃CH₃, —OCH₃, —CF₃, or —OCHF₂.
 50. The method of claim 49, wherein,in the compound or the pharmaceutically acceptable salt thereof, R^(7a)is —(CH₂)₃CH₃, —OCH₃, or —CF₃.
 51. The method of claim 47, wherein, inthe compound or the pharmaceutically acceptable salt thereof, R⁹ is—COOH, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl,2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl,3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, or1,1-dioxothiomorpholin-4-ylcarbonyl.
 52. The method of claim 51,wherein, in the compound or the pharmaceutically acceptable saltthereof, R⁹ is morpholin-4-ylcarbonyl.
 53. The method of claim 47,wherein, in the compound or the pharmaceutically acceptable saltthereof, R¹² is hydrogen or —CH₃.
 54. The method of claim 48, wherein,in the compound or the pharmaceutically acceptable salt thereof, each ofR¹², R^(13a) and R^(13b) is hydrogen and the compound has structuralformula VIIa:


55. The method of claim 31, wherein the compound is

or is a pharmaceutically acceptable salt of any of the foregoingcompounds.
 56. The method of claim 31, wherein the compound or thepharmaceutically acceptable salt thereof demonstrates a Ki against MERTKat least two times lower than its Ki against FLT3.